Stable emulsion composition

ABSTRACT

An emulsion composition comprising (1) a compound (I) represented by the formula (I) wherein each symbol is as defined in the specification (2) an anionic synthetic phospholipid in a proportion of about 0.0001 about 5% (W/V) relative to the composition in total, and (3) a naturally-occurring phospholipid in a proportion of about 0.1 about 10% (W/V) relative to the composition in total is provided.

TECHNICAL FIELD

The present invention relates to an emulsion composition having improvedstability.

BACKGROUND

WO 99/46242 describes that a compound represented by the formula:

wherein R represents an aliphatic hydrocarbon group optionally havingsubstituents, an aromatic hydrocarbon group optionally havingsubstituents, a heterocyclic group optionally having substituents, agroup represented by the formula: OR¹ (wherein R¹ represents a hydrogenatom or an aliphatic hydrocarbon group optionally having substituents)or a group represented by the formula:

(wherein R^(1b) represents a hydrogen atom or an aliphatic hydrocarbongroup optionally having substituents, R^(1c) is, same with or differentfrom R^(1b), a hydrogen atom or an aliphatic hydrocarbon groupoptionally having substituents, R⁰ represents a hydrogen atom or analiphatic hydrocarbon group, or R and R⁰ represent a bond with eachother, ring A is a cycloalkene substituted by 1 to 4 selected from (i)an aliphatic hydrocarbon group optionally having substituents, (ii) anaromatic hydrocarbon group optionally having substituents, (iii) a grouprepresented by the formula: OR¹ (wherein R¹ represents the same meaningas mentioned above) and (iv) a halogen atom, Ar represents an aromatichydrocarbon group optionally having substituents, a group represented bythe formula:

which can be a group represented by the formula:

and n is an integer of 1 to 4, and a compound represented by theformula:

wherein R^(a) represents an aliphatic hydrocarbon group optionallyhaving substituents, an aromatic hydrocarbon group optionally havingsubstituents, a heterocyclic group optionally having substituents, agroup represented by the formula: OR^(1a) (wherein R^(1a) represents ahydrogen atom or an aliphatic hydrocarbon group optionally havingsubstituents) or a group represented by the formula:

(wherein R^(1a) represents the same meaning as defined above, R^(1b) is,same with or different from R^(1a), a hydrogen atom or an aliphatichydrocarbon group optionally having substituents, R^(0a) represents ahydrogen atom or an aliphatic hydrocarbon group, or R^(a) and R^(0a)represent a bond with each other, Ar^(a) represents an aromatichydrocarbon group optionally having substituents, a group represented bythe formula:

which can be a group represented by the formula:

n represents an integer of 1 to 4, a salt thereof and a prodrug thereofhave nitric oxide (NO) production-inhibiting effect and an inhibitoryeffect on the production of inflammatory cytokines such as TNF-α, IL-1,IL-6 and the like, and are useful as a prophylactic and therapeuticagent against the diseases including cardiac diseases, autoimmunediseases, inflammatory diseases, central nervous system diseases,infectious diseases, sepsis, septic shock and the like.

This publication also describes that an oily injection can be producedby dissolving, suspending or emulsifying this compound in a vegetableoil or propylene glycol.

The present invention aims at providing an emulsion composition, whichcontains the above compound, having improved stability.

DETAILED DESCRIPTION OF THE INVENTION

The above-mentioned aim has been accomplished by the present invention.The pH of the emulsion composition containing the above-mentionedcompound is adjusted to not more than about 6, whereby the stability ofthe compound, the composition and the system has been improved andsuperior efficacy has been provided as described in further detailbelow. The present invention is based on this finding.

Accordingly, the present invention provides the following.

[1] An emulsion composition comprising (1) a compound (I) represented bythe formula:

wherein R represents an aliphatic hydrocarbon group optionally havingsubstituents, an aromatic hydrocarbon group optionally havingsubstituents, a heterocyclic group optionally having substituents, agroup represented by the formula: OR¹ (wherein R¹ represents a hydrogenatom or an aliphatic hydrocarbon group optionally having substituents)or a group represented by the formula:

(wherein R^(1b) represents a hydrogen atom or an aliphatic hydrocarbongroup optionally having substitutents, R^(1c) is, same with or differentfrom R^(1b), a hydrogen atom or an aliphatic hydrocarbon groupoptionally having substituents, R⁰ represents a hydrogen atom or analiphatic hydrocarbon group, or R and R⁰ represent a bond with eachother, ring A¹ is a cycloalkene optionally substituted by 1 to 4selected from (i) an aliphatic hydrocarbon group optionally havingsubstituents, (ii) an aromatic hydrocarbon group optionally havingsubstituents, (iii) a group represented by the formula: OR¹ (wherein R¹represents the same meaning as mentioned above) and (iv) a halogen atom,Ar represents an aromatic hydrocarbon group optionally havingsubstituents, a group represented by the formula:

can be a group represented by the formula:

and n is an integer of 1 to 4, a salt thereof or a prodrug therefor,(2) an anionic synthetic phospholipid in a proportion of about0.0001-about 5% (W/V) relative to the entire composition, and(3) a naturally-occurring phospholipid in a proportion of about0.1-about 10% (W/V) relative to the entire composition,[2] the composition of [1], wherein R is (1) {circle around (1)} linearor branched C₁₋₂₀ alkyl, {circle around (2)} C₃₋₁₀ cycloalkyl, {circlearound (3)} C₄₋₁₂ cycloalkylalkyl, {circle around (4)} lower (C₃₋₆)alkenyl group or {circle around (5)} lower (C₃₋₆) alkynyl group (whereinthe substituent selected from substituent group A may form, togetherwith {circle around (1)} linear or branched (C₁₋₂₀) alkyl, {circlearound (2)} C₃₋₁₀ cycloalkyl, {circle around (3)} C₄₋₁₂ cycloalkylalkyl,{circle around (5)} lower (C₃₋₆) alkenyl group or {circle around (5)}lower (C₃₋₆) alkynyl group, indanyl group or 1,2,3,4-tetrahydronaphthylgroup optionally having 1 to 4 substituents selected from thesubstituent group A), optionally having 1 to 4 substituents selectedfrom a group (hereinafter substituent group A) consisting of (i) a 5- to8-membered ring group or a condensed ring group containing 1 to 4 heteroatoms selected from nitrogen atom (optionally oxidized), oxygen atom andsulfur atom, which is optionally substituted by 1 to 3 substituent(s)selected from C₁₋₄ alkyl, hydroxy, oxo and C₁₋₄ alkoxy, (ii) oxo group,(iii) hydroxyl group, (iv) C₁₋₆ alkoxy group, (v) C₃₋₁₀ cycloalkyloxygroup, (vi) C₆₋₁₀ aryloxy group, (vii) C₇₋₁₉ aralkyloxy group, (viii) a5- to 8-membered ring group or a condensed ring-oxy group containing 1to 4 hetero atoms selected from nitrogen atom (optionally oxidized),oxygen atom and sulfur atom, which is optionally substituted by 1 to 3substituent(s) selected from C₁₋₄ alkyl, hydroxy, oxo and C₁₋₄ alkoxy,(ix) C₁₋₆ alkylthio group (the sulfur atom may be oxidized), (x) C₃₋₁₀cycloalkylthio group (the sulfur atom may be oxidized), (xi) C₆₋₁₀arylthio group (the sulfur atom may be oxidized), (xii) C₇₋₁₉aralkylthio group (the sulfur atom may be oxidized), (xiii) a 5- to8-membered ring group or a condensed ring-thio group containing 1 to 4hetero atoms selected from nitrogen atom (optionally oxidized), oxygenatom and sulfur atom, which is optionally substituted by 1 to 3substituent(s) selected from C₁₋₄ alkyl, hydroxy, oxo and C₁₋₄ alkoxy,(xiv) a 5- to 8-membered ring group or a condensed ring-sulfinyl groupcontaining 1 to 4 hetero atoms selected from nitrogen atom (optionallyoxidized), oxygen atom and sulfur atom, which is optionally substitutedby 1 to 3 substituent(s) selected from C₁₋₄ alkyl, hydroxy, oxo and C₁₋₄alkoxy, (xv) a 5- to 8-membered ring group or a condensed ring-sulfonylgroup containing 1 to 4 hetero atoms selected from nitrogen atom(optionally oxidized), oxygen atom and sulfur atom, which is optionallysubstituted by 1 to 3 substituent(s) selected from C₁₋₄ alkyl, hydroxy,oxo and C₁₋₄ alkoxy, (xvi) nitro group, (xvii) halogen atom, (xviii)cyano group, (xix) carboxyl group, (xx) C₁₋₁₀ alkoxy-carbonyl group,(xxi) C₃₋₆ cycloalkyloxy-carbonyl group, (xxii) C₆₋₁₀ aryloxy-carbonylgroup, (xxiii) C₇₋₁₉ aralkyloxy-carbonyl group, (xxiv) a 5- to8-membered ring group or a condensed ring-oxycarbonyl group containing 1to 4 hetero atoms selected from nitrogen atom (optionally oxidized),oxygen atom and sulfur atom, which is optionally substituted by 1 to 3substituent(s) selected from C₁₋₄ alkyl, hydroxy, oxo and C₁₋₄ alkoxy,(xxv) C₆₋₁₀ arylcarbonyl group, (xxvi) C₁₋₆ alkanoyl group, (xxvii) C₃₋₅alkenoyl group, (xxviii) C₆₋₁₀ aryl-carbonyloxy group, (xxix) C₂₋₆alkanoyloxy group, (xxx) C₃₋₅ alkenoyloxy group, (xxxi) carbamoyl groupor cyclic aminocarbonyl group optionally substituted by 1 or 2substituent(s) selected from C₁₋₄ alkyl, phenyl, C₁₋₇ acyl and C₁₋₄alkoxy-phenyl, (xxxii) thiocarbamoyl group optionally substituted by 1or 2 substituent(s) selected from C₁₋₄ alkyl and phenyl, (xxxiii)carbamoyloxy group optionally substituted by 1 or 2 substituent(s)selected from C₁₋₄ alkyl and phenyl, (xxxiv) C₁₋₆ alkanoylamino group,(xxxv) C₆₋₁₀ aryl-carbonylamino group, (xxxvi) C₁₋₁₀ alkoxy-carboxamidegroup, (xxxvii) C₆₋₁₀ aryloxy-carboxamide group, (xxxviii) C₇₋₁₉aralkyloxy-carboxamide group, (xxxix) C₁₋₁₀ alkoxy-carbonyloxy group,(xxxx) C₆₋₁₀ aryloxy-carbonyloxy group, (xxxxi) C₇₋₁₉aralkyloxy-carbonyloxy group, (xxxxii) C₃₋₁₀ cycloalkyloxy-carbonyloxygroup, (xxxxiii) ureido group optionally substituted by 1 to 3substituent(s) selected from C₁₋₄ alkyl group and phenyl group, and(xxxxiv) C₆₋₁₀ aryl group optionally having 1 to 4 substituents selectedfrom a group consisting of the above-mentioned (i)-(xxxxiii),(2) C₆₋₁₄ aromatic hydrocarbon group optionally having 1 to 5substituents selected from the group consisting of halogen atom, C₁₋₄alkyl group, C₁₋₄ alkoxy group, C₁₋₄ alkoxy-carbonyl group, carboxylgroup, nitro group, cyano group, hydroxyl group, C₁₋₄ alkanoylaminogroup, C₃₋₁₆ cycloalkyl group, C₆₋₁₀ aryl group, halogeno C₁₋₄ alkylgroup, halogeno C₁₋₄ alkoxy group, C₁₋₄ alkylthio group, C₁₋₄alkylsulfonyl group, C₁₋₄ alkanoyl group, 5-membered aromaticheterocyclic group, carbamoyl group, C₁₋₄ alkyl-carbamoyl group, C₁₋₄alkoxy-carbonyl-C₁₋₄ alkyl-carbamoyl group and 1,3-diacylguanidino-C₁₋₄alkyl group,(3) a 5- to 8-membered ring group or a condensed ring group containing 1to 4 hetero atom selected from nitrogen atom (optionally oxidized),oxygen atom and sulfur atom, which optionally has 1 to 3 substituentsselected from C₁₋₄ alkyl, hydroxy, oxo and C₁₋₄ alkoxy,(4) a group of the formula —OR¹ (wherein R¹ is (i) hydrogen atom or (ii){circle around (1)} linear or branched C₁₋₂₀ alkyl, {circle around (2)}C₃₋₁₀ cycloalkyl, {circle around (3)} C₄₋₁₂ cycloalkylalkyl, {circlearound (4)} lower (C₃₋₆) alkenyl group or {circle around (5)} lower(C₃₋₆) alkynyl group (wherein the substituent selected from substituentgroup A may form, together with {circle around (1)} linear or branchedC₁₋₂₀ alkyl, {circle around (2)} C₃₋₁₀ cycloalkyl, {circle around (3)}C₄₋₁₂ cycloalkylalkyl, {circle around (4)} lower (C₃₋₆) alkenyl group or{circle around (5)} lower (C₃₋₆) alkynyl group, indanyl group or1,2,3,4-tetrahydronaphthyl group optionally having 1 to 4 substituentsselected from the substituent group A), which optionally has 1 to 4substituents selected from the substituent group A), or(5) a group of the formula

(wherein R^(1b) is (i) hydrogen atom or (ii) {circle around (1)} linearor branched C₁₋₂₀ alkyl, {circle around (2)} C₃₋₁₀ cycloalkyl, {circlearound (3)} C₄₋₁₂ cycloalkylalkyl, {circle around (4)} lower (C₃₋₆)alkenyl group or {circle around (5)} lower (C₃₋₆) alkynyl group (whereinthe substituent selected from substituent group A may form, togetherwith {circle around (1)} linear or branched C₁₋₂₀ alkyl, {circle around(2)} C₃₋₁₀ cycloalkyl, {circle around (3)} C₄₋₁₂ cycloalkylalkyl,{circle around (4)} lower (C₃₋₆) alkenyl group or {circle around (5)}lower (C₃₋₆) alkynyl group, indanyl group or 1,2,3,4-tetrahydronaphthylgroup optionally having 1 to 4 substituents selected from thesubstituent group A), which optionally has 1 to 4 substituents selectedfrom the substituent group A), andR^(1c) is the same or different from R^(1b) and is (i) hydrogen atom or(ii) {circle around (1)} linear or branched C₁₋₂₀ alkyl, {circle around(2)} C₃₋₁₀ cycloalkyl, {circle around (3)} C₄₋₁₂ cycloalkylalkyl,{circle around (4)} lower (C₃₋₆) alkenyl group or {circle around (5)}aliphatic hydrocarbon group optionally having a substituent of lower(C₃₋₆) alkynyl group (wherein the substituent selected from substituentgroup A may form, together with {circle around (1)} linear or branchedC₁₋₂₀ alkyl, {circle around (2)} C₃₋₁₀ cycloalkyl, {circle around (3)}C₄₋₁₂ cycloalkylalkyl, {circle around (4)} lower (C₃₋₆) alkenyl group or{circle around (5)} lower (C₃₋₆) alkynyl group, indanyl group or1,2,3,4-tetrahydronaphthyl group optionally having 1 to 4 substituentsselected from the substituent group A) optionally having 1 to 4substituents selected from substituent group A),R⁰ represents a hydrogen atom, a linear or branched C₁₋₂₀ alkyl, a C₃₋₁₀cycloalkyl, a C₄₋₁₂ cycloalkylalkyl, a lower (C₃₋₆) alkenyl group or alower (C₃₋₆) alkynyl group,or R and R⁰ represent a bond with each other, ring A¹ represents(1) {circle around (1)} linear or branched C₁₋₂₀ alkyl, {circle around(2)} C₃₋₁₀ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, {circle around (4)} lower(C₃₋₆) alkenyl group or {circle around (5)} lower (C₃₋₆) alkynyl group,which optionally has 1 to 4 substituents selected from substituent groupA (wherein the substituents selected from the substituent group A mayform, together with {circle around (1)} linear or branched C₁₋₂₀ alkyl,{circle around (2)} C₃₋₁₀ cycloalkyl, {circle around (3)} C₄₋₁₂cycloalkylalkyl, {circle around (4)} lower (C₃₋₆) alkenyl group or{circle around (5)} lower (C₃₋₆) alkynyl group, indanyl group or1,2,3,4-tetrahydronaphthyl group optionally having 1 to 4 substituentsselected from the substituent group A),(2) a C₆₋₁₄ aromatic hydrocarbon group optionally having 1 to 5substituents selected from the group consisting of halogen atom, C₁₋₄alkyl group, C₁₋₄ alkoxy group, C₁₋₄ alkoxy-carbonyl group, carboxylgroup, nitro group, cyano group, hydroxyl group, C₁₋₄ alkanoylaminogroup, C₃₋₆ cycloalkyl group, C₆₋₁₀ aryl group, halogeno C₁₋₄ alkylgroup, halogeno C₁₋₄ alkoxy group, C₁₋₄ alkylthio group, C₁₋₄alkylsulfonyl group, C₁₋₄ alkanoyl group, 5-membered aromaticheterocyclic group, carbamoyl group, C₁₋₄ alkyl-carbamoyl group, C₁₋₄alkoxy-carbonyl-C₁₋₄ alkyl-carbamoyl group and 1,3-diacylguanidino-C₁₋₄alkyl group,(3) a group of the formula —OR¹ (wherein R¹ is as defined above) or(4) cycloalkene optionally substituted by 1 to 4 selected from halogenatoms, andAr represents a C₆₋₁₄ aromatic hydrocarbon group optionally having 1 to5 substituents selected from the group consisting of halogen atom, C₁₋₄alkyl group, C₁₋₄ alkoxy group, C₁₋₄ alkoxycarbonyl group, carboxylgroup, nitro group, cyano group, hydroxyl group, C₁₋₄ alkanoylaminogroup, C₃₋₆ cycloalkyl group, C₆₋₁₀ aryl group, halogeno C₁₋₄ alkylgroup, halogeno C₁₋₄ alkoxy group, C₁₋₄ alkylthio group, C₁₋₄alkylsulfonyl group, C₁₋₄ alkanoyl group, 5-membered aromaticheterocyclic group, carbamoyl group, C₁₋₄ alkyl-carbamoyl group, C₁₋₄alkoxy-carbonyl-C₁₋₄ alkyl-carbamoyl group and 1,3-diacylguanidino-C₁₋₄alkyl group,[3] the composition of [1], wherein the compound is selected from thegroup consisting of {circle around (1)} d-ethyl6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate,{circle around (2)} d-ethyl6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, {circlearound (3)} ethyl6-[N-(2-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate and {circlearound (4)} ethyl6-[N-(2-chloro-4-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, ora salt thereof,[4] the composition of [1], wherein the anionic synthetic phospholipidis a compound of the formula

wherein R⁶ and R⁷ are the same or different and each is C₇₋₂₀ chainhydrocarbon group, and R⁸ is

or a salt thereof,[5] the composition of [1], wherein the anionic synthetic phospholipidis a compound of the formula

wherein m is an integer of 7-20, and R⁸ is

or a salt thereof,[6] the composition of [1], wherein the anionic synthetic phospholipidis selected from the group consisting ofdimyristoylphoshpatidylglycerol, dipalmitoylphosphatidylglycerol,distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol,oleoylpalmitoylphosphatidylglycerol, dioctanoylphosphatidic acid,didecanoylphosphatidic acid, dilauroylphosphatidic acid,dimyristoylphosphatidic acid, dipalmitoylphosphatidic acid,diheptadecanoylphosphatidic acid, distearoylphosphatidic acid,dioleoylphosphatidic acid, arachidonylstearoylphosphatidic acid,dipalmitoylphosphatidylserine, dioleoylphosphatidylserine,dimyristoylphosphatidylinositol, dipalmitoylphosphatidylinositol,distearoylphosphatidylinositol, dioleoylphosphatidylinositol,dimyristoylphosphatidylserine and distearoylphosphatidylserine,[7] the composition of [1], wherein the anionic synthetic phospholipidis dimyristoylphosphatidylglycerol,[8] the composition of [1], wherein the naturally-occurring phospholipidis egg yolk lecithin or soybean lecithin,[9] the composition of [1], wherein the naturally-occurring phospholipidis egg yolk lecithin,[10] the composition of [1], wherein the anionic synthetic phospholipidis contained in a proportion of about 0.0001-about 2% (W/V) of thecomposition in total,[11] the composition of [1], wherein the anionic synthetic phospholipidis contained in a proportion of about 0.2% (W/V) of the composition intotal,[12] the composition of [1], which comprises the compound (I), a saltthereof or a prodrug therefor in a proportion of about 0.001-about 95 wt% of the composition in total,[13] the composition of [1], which comprises the compound (I), a saltthereof or a prodrug therefor in a proportion of about 0.01-about 30 wt% of the composition in total,[14] the composition of [1], which comprises an oil component and/orwater,[15] the composition of [14], wherein the oil component is selected fromthe group consisting of vegetable oil, a partially hydrogenatedvegetable oil, mono-acid glyceride, mixed acid glyceride and medium-sizechain fatty acid glycerine ester,[16] the composition of [14], wherein the oil component is a vegetableoil,[17] the composition of [16], wherein the vegetable oil is selected fromthe group consisting of soybean oil, cottonseed oil, rapeseed oil,peanut oil, safflower oil, sesame oil, rice bran oil, corn germ oil,sunflower oil, poppy oil and olive oil,[18] the composition of [16], wherein the vegetable oil is a soybeanoil,[19] the composition of [14], wherein the oil component is contained ina proportion of about 1-about 30 wt % of the composition in total,[20] the composition of [14], wherein the phospholipid is contained in aproportion of about 0.1-about 150 wt % of the oil component,[21] the composition of [1], which comprises glycerine,[22] the composition of [1], which is an oil-in-water composition,[23] the composition of [1], which has a pH adjusted to about 3-about 6,[24] the composition of [1], which is for an injection, [25] thecomposition of [1], which is an injectable composition comprising 1% ofd-ethyl6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate,20% of soybean oil, 1.2% of egg yolk lecithin, 0.2% (W/V) ofdimyristoylphosphatidylglycerol and water, relative to the compositionin total,[26] the composition of [1], which is an injectable compositioncomprising 1% of d-ethyl6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate,20% of soybean oil, 1.2% of egg yolk lecithin, 0.2% (W/V) ofdistearoylphosphatidylglycerol and water, relative to the composition intotal,[27] the composition of [1], which comprises a disperse phase particlecomprising anionic synthetic phospholipid, naturally-occurringphospholipid, an oil component and compound (I), a salt thereof or aprodrug therefor, and water wherein the disperse phase particle isdispersed,[28] the composition of [27], wherein the disperse phase has an averageparticle size of about 25-about 500 nm,[29] the composition of [1], which is an NO and/or cytokine productioninhibitor,[30] the composition of [1], which is an agent for preventing ortreating cardiac disease, autoimmune disease, sepsis or septic shock,[31] a method for stabilizing an emulsion composition comprising(1) a compound represented by the formula:

wherein R represents an aliphatic hydrocarbon group optionally havingsubstituents, an aromatic hydrocarbon group optionally havingsubstituents, a heterocyclic group optionally having substituents, agroup represented by the formula: OR¹ (wherein R¹ represents a hydrogenatom or an aliphatic hydrocarbon group optionally having substituents)or a group represented by the formula:

(wherein R^(1b) represents a hydrogen atom or an aliphatic hydrocarbongroup optionally having substitutents, R^(1c) is, same with or differentfrom R^(1b), a hydrogen atom or an aliphatic hydrocarbon groupoptionally having substituents, R⁰ represents a hydrogen atom or analiphatic hydrocarbon group, or R and R⁰ represent a bond with eachother, ring A¹ is a cycloalkene optionally substituted by 1 to 4selected from (i) an aliphatic hydrocarbon group optionally havingsubstituents, (ii) an aromatic hydrocarbon group optionally havingsubstituents, (iii) a group represented by the formula: OR¹ (wherein R¹represents the same meaning as mentioned above) and (iv) a halogen atom,Ar represents an aromatic hydrocarbon group optionally havingsubstituents, a group represented by the formula:

can be a group represented by the formula:

and n is an integer of 1 to 4, a salt thereof or a prodrug therefor,(2) an anionic synthetic phospholipid in a proportion of about0.0001-about 5% (W/V) relative to the composition in total, and(3) a naturally-occurring phospholipid in a proportion of about0.1-about 10% (W/V) relative to the composition in total,wherein said composition is adjusted to have a pH of not more than 6,[32] the stabilizing method of [31], wherein the stability duringautoclave sterilization is improved,[33] a method for preventing or treating cardiac disease, autoimmunedisease, sepsis or septick shock, which comprises administrating to amammal an effective amount of the composition of [1], and[34] use of the composition of [1] for manufacturing an agent forpreventing or treating cardiac disease, autoimmune disease, sepsis orseptick shock.

The present invention also provides

[35] the composition of [1], wherein the compound of the formula (I) isa compound represented by the formula:

wherein R represents an aliphatic hydrocarbon group optionally havingsubstituents, an aromatic hydrocarbon group optionally havingsubstituents, a heterocyclic group optionally having substituents, agroup represented by the formula: OR¹ (wherein R¹ represents a hydrogenatom or an aliphatic hydrocarbon group optionally having substituents)or a group represented by the formula:

(wherein R^(1b) represents a hydrogen atom or an aliphatic hydrocarbongroup optionally having substituents, R^(1c) is, same with or differentfrom R^(1b), a hydrogen atom or an aliphatic hydrocarbon groupoptionally having substituents), R⁰ represents a hydrogen atom or analiphatic hydrocarbon group, or R and R⁰ represent a bond with eachother, ring A² is a cycloalkene substituted by 1 to 4 substituentsselected from (i) an aliphatic hydrocarbon group optionally havingsubstituents, (ii) an aromatic hydrocarbon group optionally havingsubstituents, (iii) a group represented by the formula: OR¹ (wherein R¹represents the same meaning as mentioned above) and (iv) a halogen atom,Ar represents an aromatic hydrocarbon group optionally havingsubstituents, a group represented by the formula:

can be a group represented by the formula:

and n is an integer of 1 to 4, or a compound represented by the formula:

wherein R^(a) represents an aliphatic hydrocarbon group optionallyhaving substituents, an aromatic hydrocarbon group optionally havingsubstituents, a heterocyclic group optionally having substituents, agroup represented by the formula: OR^(1a) (wherein R^(1a) represents ahydrogen atom or an aliphatic hydrocarbon group optionally havingsubstituents) or a group represented by the formula:

(wherein R^(a) represents the same meaning as defined above, R¹ is, samewith or different from R^(1a), a hydrogen atom or an aliphatichydrocarbon group optionally having substituents, R^(1a) represents ahydrogen atom or an aliphatic hydrocarbon group, or R^(a) and R^(0a)represent a bond with each other, Ar^(a) represents an aromatichydrocarbon group optionally having substituents, a group represented bythe formula:

can be a group represented by the formula:

n represents an integer of 1 to 4,[36] the composition of [35], wherein the compound represented by theformula (Iaa) is a compound represented by the formula:

wherein each symbols represents the same meaning as defined in [35],[37] the composition of [35], wherein the ring A² is a cycloalkenesubstituted by lower alkyl, phenyl or halogen, R¹ is a lower alkylgroup, Ar is a phenyl group optionally having substituents, and n is 2,[38] the composition of [35], wherein the compound represented by theformula (Ie) is a compound of the formula:

wherein R represents an aliphatic hydrocarbon group optionally havingsubstituents, an aromatic hydrocarbon group optionally havingsubstituents, a heterocyclic group optionally having substituents, agroup represented by the formula: OR¹ (wherein R¹ represents a hydrogenatom or an aliphatic hydrocarbon group optionally having substituents)or a group represented by the formula:

(wherein R^(1b) represents a hydrogen atom or an aliphatic hydrocarbongroup optionally having substituents, R^(1c) is, same with or differentfrom R^(1b), a hydrogen atom or an aliphatic hydrocarbon groupoptionally having substituents), R⁰ represents a hydrogen atom or analiphatic hydrocarbon group, or R and R⁰ represent a bond with eachother, Ar represents an aromatic hydrocarbon group optionally havingsubstituents, a group represented by the formula:

can be a group represented by the formula:

and n is an integer of 1 to 4, provided that when n is 1 or 2 and (i) R¹is a hydrogen atom or an ethyl group, R⁰ is a methyl group and Ar is aphenyl group or (ii) R and R⁰ represent a bond with each other and Ar isa phenyl group, a 2-methylphenyl group, a 4-bromophenyl group, a4-methoxyphenyl group or a 2,6-dimethylphenyl group, a group representedby the formula:

is a group represented by the formula:

[39] the composition of [38], wherein the compound represented by theformula (Ia) is a compound represented by the formula:

wherein R² represents a hydrogen atom or an aliphatic hydrocarbon group,R¹, Ar, n and the group represented by the formula:

represent the same meanings defined in [38], provided that when n is 1or 2, Ar is a phenyl group, R¹ is a hydrogen atom or an ethyl group andR² is a methyl group, the group represented by the formula:

is a group represented by the formula:

[40] the composition of [39], wherein R¹ is a lower alkyl groupoptionally having substituents,[41] the composition of [39], wherein R¹ is an ethyl group,[42] the composition of [39], wherein R² is a hydrogen atom or a loweralkyl group,[43] the composition of [39], wherein R² is a hydrogen atom,[44] the composition of [39], wherein Ar is a phenyl group optionallyhaving substituents,[45] the composition of [39], wherein Ar is a phenyl group substitutedby halogen or/and lower alkyl,[46] the composition of [39], wherein Ar is a group represented by theformula:

wherein R⁴ and R⁵ are same or different and represents a halogen atom ora lower alkyl group, and n is an integer of 0 to 2,[47] the composition of [39], wherein the halogen atom is a fluoro atomor a chloro atom,[48] the composition of [39], wherein the group represented by theformula:

is a group represented by the formula:

wherein n represents the same meaning as defined in [39],[49] the composition of [39], wherein n is 1 to 3,[50] the composition of [39], wherein R¹ is a lower alkyl groupoptionally having substituents, R² is a hydrogen atom or a lower alkylgroup, Ar is a phenyl group optionally having substituents, n is 1, 2 or3,[51] the composition of [39], wherein R¹ is a lower alkyl groupoptionally having substituents, R² is a hydrogen atom, Ar is a phenylgroup substituted by a halogen atom, and n is 2,[52] the composition of [38], wherein the compound represented by theformula (Ia) is a compound represented by the formula:

wherein Ar and n represent the same meanings as defined in [38],[53] the composition of [52], wherein Ar is a phenyl group optionallyhaving substituents, and n is 2,[54] the composition of [38], wherein the compound represented by theformula (Ia) is a compound represented by the formula:

wherein R¹, R² and Ar represent the same meanings as defined in [39],the group represented by the formula:

is a group represented by the formula:

provided that when Ar is a phenyl group, R¹ is a hydrogen atom or anethyl group and R² is a methyl group and the group represented by theformula:

is a group represented by the formula:

[55] the composition of [35], wherein the compound represented by theformula (Ie) is a compound represented by the formula:

wherein R^(2a) represents a hydrogen atom or an aliphatic hydrocarbongroup, R^(1a), Ar^(a), n and the group represented by the formula:

represent the same meanings as defined in [35], and [56] the compositionof [35], wherein the compound represented by the formula (Ie) is acompound represented by the formula:

wherein R^(1a), R^(2a) and Ar^(a) represent the same meanings as definedin [55] and the group represented by the formula:

is a group represented by the formula:

In the specification, R represents an aliphatic hydrocarbon groupoptionally having substituents, an aromatic hydrocarbon group optionallyhaving substituents, a heterocyclic group optionally havingsubstituents, a group represented by the formula: OR¹ (wherein R¹represents a hydrogen atom or an aliphatic hydrocarbon group optionallyhaving substituents) or a group represented by the formula:

wherein R^(1b) represents a hydrogen atom or an aliphatic hydrocarbongroup optionally having substituents, R^(1c) is, same with or differentfrom R^(1b), a hydrogen atom or an aliphatic hydrocarbon groupoptionally having substituents, or R forms a bond with R⁰, and amongthem the group represented by the formula: OR¹ (wherein R¹ representsthe same meaning as defined above) is preferred.

And, R^(a) represents an aliphatic hydrocarbon group optionally havingsubstituents, an aromatic hydrocarbon group optionally havingsubstituents, a heterocyclic group optionally having substituents, agroup represented by the formula: OR^(1a) (wherein R^(1a) represents ahydrogen atom or an aliphatic hydrocarbon group optionally havingsubstituents) or a group represented by the formula:

(wherein R^(1a) represents the same meaning as defined above, R^(1b) is,same with or different from R^(1a), a hydrogen atom or an aliphatichydrocarbon group optionally having substituents), or form a bond withR^(0a), and among them the group represented by the formula: OR^(1a)(wherein R^(1a) represents the same meaning as defined above) ispreferred.

When R and R⁰ represent a bond with each other, the compound representedby the formula (Iaa) can be represented by the formula:

wherein each symbol represents the same meaning as defined above, andspecifically can be represented by the formula:

wherein each symbol represents the same meaning as defined above, or theformula:

wherein each symbol represents the same meaning as defined above.

When R and R⁰ represent a bond with each other, the compound representedby the formula (Ia) can be represented by the formula:

wherein each symbol represents the same meaning as defined above, andspecifically can be represented by the formula:

wherein each symbol represents the same meaning as defined above, or theformula:

wherein each symbol represents the same meaning as defined above.

When R^(a) and R^(0a) represent a bond with each other, the compoundrepresented by the formula (Ie) can be represented by the formula:

wherein each symbol represents the same meaning as defined above, andspecifically can be represented by the formula:

wherein each symbol represents the same meaning as defined above, or theformula:

wherein each symbol represents the same meaning as defined above.

When R is a group represented by the formula: OR¹ (wherein R¹ representsthe same meaning as defined above), the compound represented by theformula (Iaa) can be represented by the formula:

wherein each symbol represents the same meaning as defined above, andspecifically can be represented by the formula:

wherein each symbol represents the same meaning as defined above, or theformula:

wherein each symbol represents the same meaning as defined above.

When R is a group represented by the formula: OR¹ (wherein R¹ representsthe same meaning as defined above), the compound represented by theformula (Ia) can be represented by the formula:

wherein each symbol represents the same meaning as defined above, andspecifically can be represented by the formula:

wherein each symbol represents the same meaning as defined above, or theformula:

wherein each symbol represents the same meaning as defined above.

When R^(a) is a group represented by the formula: OR^(1a) (whereinR^(1a) represents the same meaning as defined above), the compoundrepresented by the formula (Ie) can be represented by the formula:

wherein each symbol represents the same meaning as defined above, andspecifically can be represented by the formula:

wherein each symbol represents the same meaning as defined above, or theformula:

wherein each symbol represents the same meaning as defined above.

As the compound represented by the formula (Iaa), the compoundrepresented by the formula (Icc) or the formula (Inn) is preferred, asthe compound represented by the formula (Ia), the compound representedby the formula (Ic) or the formula (In) are preferred, and as thecompound represented by the formula (Ie), the compound represented bythe formula (Ik) or the formula (Ip) are preferred,

Similarly, the compound represented by the formula (Id) can berepresented by the formula:

wherein each symbol represents the same meaning as defined above, or theformula:

wherein each symbol represents the same meaning as defined above, andthe compound represented by the formula (Ig) can be represented by theformula:

wherein each symbol represents the same meaning as defined above, or theformula:

wherein each symbol represents the same meaning as defined above.

As the compound represented by the formula (Id), the compoundrepresented by the formula (Ir) is preferred, as the compoundrepresented by the formula (Ig), the compound represented by the formula(It) is preferred.

In the compound represented by the formula (Ia), when n is 1 or 2, and(i) R¹ is a hydrogen atom or an ethyl group, R⁰ is a methyl group and Aris a phenyl group, or (ii) R and R⁰ represent a bond with each other andAr is a phenyl group, a 2-methylphenyl group, a 4-bromophenyl group, a4-methoxyphenyl group or a 2,6-dimethylphenyl group,

a group represented by the formula:

Furthermore, when n is 1 to 4, and (i) R¹ is a hydrogen atom or a loweralkyl group optionally having substituents, R¹ is a lower alkyl groupoptionally having substituents, and Ar is a phenyl group optionallyhaving substituents, or (ii) R and R⁰ represent a bond with each otherand Ar is a phenyl group optionally having substituents, a grouprepresented by the formula:

In the compound represented by the formula (Ib), when n is 1 or 2, R¹ isa hydrogen atom or an ethyl group, R⁰ is a methyl group, and Ar is aphenyl group, a group represented by the formula:

Furthermore, when n is 1 to 4, and R¹ is a hydrogen atom or a loweralkyl group optionally having substituents, R⁰ is a lower alkyl groupoptionally having substituents, and Ar is a phenyl group optionallyhaving substituents, a group represented by the formula:

Thus, in one embodiment, the present invention provides for an emulsioncomposition comprising a compound of the formula:

wherein R represents an optionally substituted aliphatic hydrocarbongroup, an optionally substituted aromatic hydrocarbon group, anoptionally substituted heterocyclic group, a group represented by theformula: OR¹ where R¹ represents a hydrogen atom or an optionallysubstituted aliphatic hydrocarbon group, or a group represented by theformula:

where R^(1b) and R^(1c) are each independently a hydrogen atom or anoptionally substituted aliphatic hydrocarbon group), R⁰ represents ahydrogen atom or an optionally substituted aliphatic hydrocarbon group,or taken together, R and R⁰ represent a bond,

wherein n is an integer of 1 to 4, ring A¹ is a cycloalkene optionallysubstituted by 1 to 4 substituents selected from the group consisting of(i) an aliphatic hydrocarbon group optionally having substituents, (ii)an aromatic hydrocarbon group optionally having substituents, (iii) agroup represented by the formula: OR¹ where R¹ represents a hydrogenatom or an aliphatic hydrocarbon group optionally having substituents,and (iv) a halogen atom, Ar represents an optionally substitutedaromatic hydrocarbon group, a salt thereof or a prodrug therefor, (2) ananionic synthetic phospholipid in a proportion of about 0.0001 to about5% weight per total volume relative to the composition in total, and (3)a naturally-occurring phospholipid in a proportion of about 0.1 to about10% weight per total volume relative to the composition in total.

The present invention also provides for such an emulsion compositionwherein R, R¹, R^(1b), R^(1c), R^(1d), A¹ and Ar may be substituted withone to four substituents, each substituent independently selected fromthe group of substituents collectively identified as group Q.

The substituents of group Q consisting of (i) a 5- to 8-membered ring orcondensed ring substituent group containing 1 to 4 hetero atoms selectedfrom the group consisting of nitrogen atom which is optionally oxidized,oxygen atom and sulfur atom, where said ring is optionally substitutedby 1 to 3 substituents selected from the group consisting of C₁₋₄ alkyl,hydroxy, oxo and C₁₋₄ alkoxy, (ii) oxo substituent group, (iii) hydroxylsubstituent group, (iv) C₁₋₆ alkoxy substituent group, (v) C₃₋₁₀cycloalkyloxy substituent group, (vi) C₆₋₁₀ aryloxy substituent group,(vii) C₇₋₁₉ aralkyloxy substituent group, (viii) a 5- to 8-membered ringor condensed ring-oxy substituent group containing 1 to 4 hetero atomsselected from the group consisting of nitrogen atom which is optionallyoxidized, oxygen atom and sulfur atom, where said ring-oxy substituentgroup is optionally substituted by 1 to 3 substituents selected from thegroup consisting of C₁₋₄ alkyl, hydroxy, oxo and C₁₋₄ alkoxy, (ix) C₁₋₆alkylthio substituent group where the sulfur atom may be optionallyoxidized, (x) C₃₋₁₀ cycloalkylthio substituent group where the sulfuratom may be optionally oxidized, (xi) C₆₋₁₀ arylthio substituent groupwhere the sulfur atom may be optionally oxidized, (xii) C₇₋₁₉aralkylthio substituent group where the sulfur atom may be optionallyoxidized, (xiii) a 5- to 8-membered ring or condensed ring-thiosubstituent group containing 1 to 4 hetero atoms selected from the groupconsisting of nitrogen atom which is optionally oxidized, oxygen atomand sulfur atom, where said ring-thio substituent group is optionallysubstituted by 1 to 3 substituents selected from the group consisting ofC₁₋₄ alkyl, hydroxy, oxo and C₁₋₄ alkoxy, (xiv) a 5- to 8-membered ringor condensed ring-sulfinyl substituent group containing 1 to 4 heteroatoms selected from the group consisting of nitrogen atom which isoptionally oxidized, oxygen atom and sulfur atom, where saidring-sulfinyl substituent group is optionally substituted by 1 to 3substituents selected from the group consisting of C₁₋₄ alkyl, hydroxy,oxo and C₁₋₄ alkoxy, (xv) a 5- to 8-membered ring group or a condensedring-sulfonyl group containing 1 to 4 hetero atoms selected from thegroup consisting of nitrogen atom which is optionally oxidized, oxygenatom and sulfur atom, where said ring-sulfonyl substituent group isoptionally substituted by 1 to 3 substituents selected from the groupconsisting of C₁₋₄ alkyl, hydroxy, oxo and C₁₋₄ alkoxy, (xvi) nitrosubstituent group, (xvii) halogen atom, (xviii) cyano substituent group,(xix) carboxyl substituent group, (xx) C₁₋₁₀ alkoxy-carbonyl substituentgroup, (xxi) C₃₋₆ cycloalkyloxy-carbonyl substituent group, (xxii) C₆₋₁₀aryloxy-carbonyl substituent group, (xxiii) C₇₋₁₉ aralkyloxy-carbonylsubstituent group, (xxiv) a 5- to 8-membered ring or condensedring-oxycarbonyl substituent group containing 1 to 4 hetero atomsselected from the group consisting of nitrogen atom which is optionallyoxidized, oxygen atom and sulfur atom, where said ring-oxycarbonylsubstituent group is optionally substituted by 1 to 3 substituentsselected from the group consisting of C₁₋₄ alkyl, hydroxy, oxo and C₁₋₄alkoxy, (xxv) C₆₋₁₀ arylcarbonyl substituent group, (xxvi) C₁₋₆ alkanoylsubstituent group, (xxvii) C₃₋₅ alkenoyl substituent group, (xxviii)C₆₋₁₀ aryl-carbonyloxy substituent group, (xxix) C₂₋₆ alkanoyloxysubstituent group, (xxx) C₃₋₅ alkenoyloxy substituent group, (xxxi)carbamoyl substituent group or cyclic aminocarbonyl substituent groupoptionally substituted by 1 or 2 substituents selected from the groupconsisting of C₁₋₄ alkyl, phenyl, C₁₋₇ acyl and C₁₋₄ alkoxy-phenyl,(xxxii) thiocarbamoyl substituent group optionally substituted by 1 or 2substituents selected from the group consisting of C₁₋₄ alkyl andphenyl, (xxxiii) carbamoyloxy substituent group optionally substitutedby 1 or 2 substituents selected from the group consisting of C₁₋₄ alkyland phenyl, (xxxiv) C₁₋₆ alkanoylamino substituent group, (xxxv) C₆₋₁₀aryl-carbonylamino substituent group, (xxxvi) C₁₋₁₀ alkoxy-carboxamidesubstituent group, (xxxvii) C₆₋₁₀ aryloxy-carboxamide substituent group,(xxxviii) C₇₋₁₉ aralkyloxy-carboxamide substituent group, (xxxix) C₁₋₁₀alkoxy-carbonyloxy substituent group, (xxxx) C₆₋₁₀ aryloxy-carbonyloxysubstituent group, (xxxxi) C₇₋₁₉ aralkyloxy-carbonyloxy substituentgroup, (xxxxii) C₃₋₁₀ cycloalkyloxy-carbonyloxy substituent group,(xxxxiii) ureido substituent group optionally substituted by 1 to 3substituents selected from the group consisting of C₁₋₄ alkyl andphenyl, and (xxxxiv) C₆₋₁₀ aryl substituent group optionally having 1 to4 substituents selected from the group consisting of C₁₋₄ alkyl andphenyl.

The present invention further provides for an emulsion composition asdescribed above, wherein R is (1) {circle around (1)} linear or branchedC₁₋₂₀ alkyl, {circle around (2)} C₃₋₁₀ cycloalkyl, {circle around (3)}C₄₋₁₂ cycloalkylalkyl, {circle around (4)} lower (C₃₋₆) alkenyl group or{circle around (5)} lower (C₃₋₆) alkynyl group optionally having 1 to 4substituents each independently selected from the group Q; wherein whentwo substituents from group Q substitute said linear or branched C₁₋₂₀alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, C₃₋₆ alkenyl or C₃₋₆alkynyl, said substituents may be linked to form a ring; (2) C₆₋₁₄aromatic hydrocarbon group optionally having 1 to 5 substituentsselected from the group consisting of halogen atom, C₁₋₄ alkyl group,C₁₋₄ alkoxy group, C₁₋₄ alkoxy-carbonyl group, carboxyl group, nitrogroup, cyano group, hydroxyl group, C₁₋₄ alkanoylamino group, C₃₋₁₆cycloalkyl group, C₆₋₁₀ aryl group, halogeno C₁₋₄ alkyl group, halogenoC₁₋₄ alkoxy group, C₁₋₄ alkylthio group, C₁₋₄ alkylsulfonyl group, C₁₋₄alkanoyl group, 5-membered aromatic heterocyclic group, carbamoyl group,C₁₋₄ alkyl-carbamoyl group, C₁₋₄ alkoxy-carbonyl-C₁₋₄ alkyl-carbamoylgroup and 1,3-diacylguanidino-C₁₋₄ alkyl group, (3) a 5- to 8-memberedring or a condensed ring group containing 1 to 4 hetero atoms selectedfrom the group consisting of nitrogen atom which is optionally oxidized,oxygen atom and sulfur atom, where said ring group optionally has 1 to 3substituents selected from the group consisting of C₁₋₄ alkyl, hydroxy,oxo and C₁₋₄ alkoxy, (4) a group of the formula —OR¹ wherein R¹ is (i)hydrogen atom or (ii) {circle around (1)} linear or branched C₁₋₂₀alkyl, {circle around (2)} C₃₋₁₀ cycloalkyl, {circle around (3)} C₄₋₁₂cycloalkylalkyl, {circle around (4)} lower C₃₋₆ alkenyl group or {circlearound (5)} lower C₃₋₆ alkynyl group optionally having 1 to 4substituents, each independently selected from the group Q; wherein whentwo substituents from group Q substitute said linear or branched C₁₋₂₀alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, C₃₋₆ alkenyl or C₃₋₆alkynyl, said substituents may be linked to form a ring; or (5) a groupof the formula

wherein R^(1b) and R^(1c) are each independently a (i) hydrogen atom or(ii) {circle around (1)} linear or branched C₁₋₂₀ alkyl, {circle around(2)} C₃₋₁₀ cycloalkyl, {circle around (3)} C₄₋₁₂ cycloalkylalkyl,{circle around (4)} lower C₃₋₆ alkenyl group or {circle around (5)}lower C₃₋₆ alkynyl group optionally substituted with 1 to foursubstituents each independently selected from the group Q; wherein whentwo substituents from group Q substitute said linear or branched C₁₋₂₀alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, C₃₋₆ alkenyl or C₃₋₆alkynyl, said substituents may be linked to form a ring; R⁰ represents ahydrogen atom, a linear or branched C₁₋₂₀ alkyl, a C₃₋₁₀ cycloalkyl, aC₄₋₁₂ cycloalkylalkyl, a lower (C₃₋₆) alkenyl group or a lower (C₃₋₆)alkynyl group, or R and R⁰ represent a bond with each other, ring A¹represents cycloalkene optionally substituted by 1 to 4 substituents,each independently selected from the group consisting of linear orbranched C₁₋₂₀ alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, C₃₋₆alkenyl or C₃₋₆ alkynyl; optionally substituted with 1 to foursubstituents, each of said substituents independently selected fromsubstituent group Q; wherein when two substituents from group Qsubstitute said linear or branched C₁₋₂₀ alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₂cycloalkylalkyl, C₃₋₆ alkenyl or C₃₋₆ alkynyl, said substituents may belinked to form a ring; (2) a C₆₋₁₄ aromatic hydrocarbon group optionallyhaving 1 to 5 substituents selected from the group consisting of halogenatom, C₁₋₄ alkyl group, C₁₋₄ alkoxy group, C₁₋₄ alkoxy-carbonyl group,carboxyl group, nitro group, cyano group, hydroxyl group, C₁₋₄alkanoylamino group, C₃₋₆ cycloalkyl group, C₆₋₁₀ aryl group, halogenoC₁₋₄ alkyl group, halogeno C₁₋₄ alkoxy group, C₁₋₄ alkylthio group, C₁₋₄alkylsulfonyl group, C₁₋₄ alkanoyl group, 5-membered aromaticheterocyclic group, carbamoyl group, C₁₋₄ alkyl-carbamoyl group, C₁₋₄alkoxy-carbonyl-C₁₋₄ alkyl-carbamoyl group and 1,3-diacylguanidino-C₁₋₄alkyl group; (3) —OR¹ wherein R¹ is (i) hydrogen atom or (ii) {circlearound (1)} linear or branched C₁₋₂₀ alkyl, {circle around (2)} C₃₋₁₀cycloalkyl, {circle around (3)} C₄₋₁₂ cycloalkylalkyl, {circle around(4)} lower C₃₋₆ alkenyl group or {circle around (5)} lower C₃₋₆ alkynylgroup optionally having 1 to 4 substituents, each independently selectedfrom the group Q; wherein when two substituents from group Q substitutesaid linear or branched C₁₋₂₀ alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₂cycloalkylalkyl, C₃₋₆ alkenyl or C₃₋₆ alkynyl, said substituents may belinked to form a ring; (4) halogen atoms and, Ar represents a C₆₋₁₄aromatic hydrocarbon group optionally having 1 to 5 substituentsselected from the group consisting of halogen atom, C₁₋₄ alkyl group,C₁₋₄ alkoxy group, C₁₋₄ alkoxycarbonyl group, carboxyl group, nitrogroup, cyano group, hydroxyl group, C₁₋₄ alkanoylamino group, C₃₋₆cycloalkyl group, C₆₋₁₀ aryl group, halogeno C₁₋₄ alkyl group, halogenoC₁₋₄ alkoxy group, C₁₋₄ alkylthio group, C₁₋₄ alkylsulfonyl group, C₁₋₄alkanoyl group, 5-membered aromatic heterocyclic group, carbamoyl group,C₁₋₄ alkyl-carbamoyl group, C₁₋₄ alkoxy-carbonyl-C₁₋₄ alkyl-carbamoylgroup and 1,3-diacylguanidino-C₁₋₄ alkyl group.

The present invention further provides for an emulsion composition, asdescribed above, wherein when two substituents from group Q substitutesaid linear or branched C₁₋₂₀ alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₂cycloalkylalkyl, C₃₋₆ alkenyl or C₃₋₆ alkynyl, said substituents may belinked to form a ring; wherein said ring is an indanyl group or a1,2,3,4-tetrahydronaphthyl group; and wherein said ring may be furthersubstituted by 1 to 4 substituents each independently selected fromgroup Q.

The present invention provides for an emulsion composition, wherein saidanionic synthetic phospholipid is a compound of the formula

wherein R⁶ and R⁷ are the same or different and each is a C₇₋₂₀ chainhydrocarbon group, and R⁸ is

or a salt thereof.

The present invention provides for an emulsion composition as describedabove, wherein said anionic synthetic phospholipid is a compound of theformula

wherein m is an integer of 7-20, and R⁸ is

or a salt thereof.

Thus, in one embodiment, the present invention provides for an emulsioncomposition as described, wherein said anionic synthetic phospholipid isdimyristoylphosphatidylglycerol. The present invention provides for anemulsion composition wherein said naturally-occurring phospholipid isegg yolk lecithin or soybean lecithin. In a preferred embodiment, saidnaturally-occurring phospholipid is egg yolk lecithin.

The present invention provides for an emulsion composition comprisingabout 0.1 to about 3% weight per total volume of d-ethyl6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate,about 5 to about 25% weight per total volume of soybean oil, about 1 toabout 3% weight per total volume of egg yolk lecithin, about 0.05 toabout 0.5% weight per total volume dimyristoyl phosphatidylglycerol andwater.

The present invention provides for an emulsion composition comprisingabout 0.1 to about 3% weight per total volume of d-ethyl6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate,about 5 to about 25% weight per total volume of soybean oil, about 1 toabout 3% weight per total volume of egg yolk lecithin, about 0.05 toabout 0.5% weight per total volume distearoyl phosphatidylglycerol andwater.

The present invention further provides for an emulsion composition asdescribed, wherein said anionic synthetic phospholipid is contained in aproportion of about 0.0001 to about 2% weight per total volume of thecomposition in total. Further, the invention provides for an emulsioncomposition, wherein said anionic synthetic phospholipid is contained ina proportion of about 0.2% weight per total volume of the composition intotal.

The present invention further provides for an emulsion composition asdescribed, wherein a compound of formula (I), a salt thereof or aprodrug therefor is in a proportion of about 0.001 to about 95 weightpercent of the composition in total. Further, the invention provides foran emulsion composition, wherein a compound of formula (I), a saltthereof or a prodrug therefor is in a proportion of about 0.01 to about30 weight percent of the composition in total.

The present invention provides for an emulsion composition as described,which further comprises a component selected from the group consistingof oil, water and a combination thereof. Further, the invention providesfor an emulsion composition, further comprising an oil which is selectedfrom the group consisting of vegetable oil, a partially hydrogenatedvegetable oil, mono-acid glyceride, mixed acid glyceride and medium-sizechain fatty acid glycerine ester. In a preferred embodiment, the oil isa vegetable oil. The present invention provides for an emulsioncomposition, wherein said vegetable oil is selected from the groupconsisting of soybean oil, cottonseed oil, rapeseed oil, peanut oil,safflower oil, sesame oil, rice bran oil, corn germ oil, sunflower oil,poppy oil and olive oil. A preferred vegetable oil is a soybean oil.

The present invention provides for an emulsion composition, wherein oilis in a proportion of about 1 to about 30 weight percent of thecomposition in total. Further, the invention provides for an emulsioncomposition, which further comprises glycerine.

The invention provides for an emulsion composition, which is anoil-in-water composition.

The invention provides for an emulsion composition, which has a pH fromabout 3 to about 6.

The invention provides for an emulsion composition, which is for aninjection.

The invention provides for an emulsion composition comprising: about 1%weight per total volume of d-ethyl6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate,about 20% weight per total volume of soybean oil, about 1.2% weight pertotal volume of egg yolk lecithin, and about 0.2% weight per totalvolume dimyristoyl phosphatidylglycerol and water.

The invention provides for an emulsion composition comprising: about 1%weight per total volume of d-ethyl6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate,about 20% weight per total volume of soybean oil, about 1.2% weight pertotal volume of egg yolk lecithin, about 0.2% weight per total volumedistearoyl phosphatidylglycerol and water.

The invention provides for an emulsion composition, as described above,which comprises a disperse phase particle comprising anionic syntheticphospholipid, naturally-occurring phospholipid, an oil component andcompound (I), a salt thereof or a prodrug therefor, and water whereinthe disperse phase particle is dispersed.

The invention provides for an emulsion composition wherein the dispersephase has an average particle size of about 25 to about 500 nm.

The invention provides for an emulsion composition which is a nitricoxide or cytokine production inhibitor, or a nitric oxide inhibitor anda cytokine production inhibitor.

The invention provides for an emulsion composition which is an agent fortreating cardiac disease, autoimmune disease, sepsis or septic shock.

The invention further provides for a method for making an emulsioncomposition, as described, comprising the steps of: (a) adding ananionic synthetic phospholipid, and a naturally-occurring phospholipidto a compound represented by the formula:

as described above, wherein R represents an optionally substitutedaliphatic hydrocarbon group, an optionally substituted aromatichydrocarbon group, an optionally substituted heterocyclic group, a grouprepresented by the formula: OR¹ where R¹ represents a hydrogen atom oran optionally substituted aliphatic hydrocarbon group, or a grouprepresented by the formula:

where R^(1b) and R³C are each independently a hydrogen atom or anoptionally substituted aliphatic hydrocarbon group, R⁰ represents ahydrogen atom or an optionally substituted aliphatic hydrocarbon group,or taken together, R and R⁰ represent a bond,

wherein n is an integer of 1 to 4,ring A¹ is a cycloalkene optionally substituted by 1 to 4 substituentsselected from the group consisting of (i) an aliphatic hydrocarbon groupoptionally having substituents, (ii) an aromatic hydrocarbon groupoptionally having substituents, (iii) a group represented by theformula: OR1 where R1 represents a hydrogen atom or an aliphatichydrocarbon group optionally having substituents, and (iv) a halogenatom, Ar represents an optionally substituted aromatic hydrocarbongroup, a salt thereof or a prodrug therefor, in oil and water to form anemulsion; and then, (b) adjusting said emulsion to a pH of not more thanabout 6 to form a stable emulsion.

The invention provides for a method, as described, whereby stability ofsaid stable emulsion during autoclave sterilization is improved.

The invention provides for a method for treating cardiac disease,autoimmune disease, sepsis or septic shock, comprising administrating toa mammal in need thereof a pharmaceutically effective amount of theemulsion composition described above.

The present invention provides for use of the emulsion composition ofthe invention for manufacturing an agent for preventing or treatingcardiac disease, autoimmune disease, sepsis or septic shock.

As the “aliphatic hydrocarbon group” of the “aliphatic hydrocarbon groupoptionally having substituents” (optionally substituted aliphatichydrocarbon group) represented by R, R¹, R^(1a), R^(1b), R^(1c), and the“aliphatic hydrocarbon group” represented by R⁰, R^(0a), R², R^(2a), forexample, an alkyl group, a cycloalkyl group, a cycloalkylalkyl group, analkenyl group, an alkynyl group, etc. are preferred.

As the alkyl group, for example, a linear or branched alkyl group having1 to 20 carbons (e.g., a methyl group, an ethyl group, a n-propyl group,an isopropyl group, a n-butyl group, an isobutyl group, a sec-butylgroup, a tert-butyl group, a pentyl group, a hexyl group, a heptylgroup, an octyl group, a nonyl group, a decyl group, a dodecyl group,etc.), etc. are preferred, and particularly, for example, a lower alkylgroup having 1 to 6 carbons (e.g., a methyl group, an ethyl group, an-propyl group, an isopropyl group, a n-butyl group, an isobutyl group,a sec-butyl group, a tert-butyl group, etc.), etc. are preferred.

As the cycloalkyl group, for example, a cycloalkyl group having 3 to 10carbons (e.g., a cyclopropyl group, a cyclobutyl group, a cyclopentylgroup, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group,etc.), etc. are preferred, and particularly, for example, a cycloalkylgroup having 3 to 6 carbons (e.g., a cyclopropyl group, a cyclobutylgroup, a cyclopentyl group, a cyclohexyl group, etc.), etc. arepreferred.

As the cycloalkylalkyl group, for example, a cycloalkylalkyl grouphaving 4 to 12 carbons (e.g., a cyclopropylmethyl group, acyclopentylmethyl group, a cyclohexylmethyl group, a cycloheptylmethylgroup, etc.), etc. are preferred, and particularly, for example, acycloalkylalkyl group having 4 to 8 (particularly, 4 to 7) carbons(e.g., a cyclopropylmethyl group, a cyclopentylmethyl group, acyclohexylmethyl group, etc.), etc. are preferred.

As the alkenyl group, for example, a lower alkenyl group having 3 to 6carbons (e.g., a propenyl group, a butenyl group, a pentenyl group,etc.), and particularly, for example, a lower alkenyl group having 3 or4 carbons (e.g., a propenyl group, a butenyl group, etc.), etc. arepreferred.

As the alkynyl group, for example, a lower alkynyl group having 3 to 6carbons (e.g., a propynyl group, a butynyl group, a pentynyl group,etc.), and particularly, for example, a lower alkenyl group having 3 or4 carbons (e.g., a propynyl group, a butynyl group, etc.), etc. arepreferred.

As the “substituents” of the above mentioned “aliphatic hydrocarbongroup optionally having substituents” (optionally substituted aliphatichydrocarbon group), for example, a heterocyclic group, an oxo group, ahydroxy group, a C₁₋₆ alkoxy group, a C₃₋₁₀ (particularly, C₃₋₆)cycloalkyloxy group, a C₆₋₁₀ aryloxy group, a C₇₋₁₉ (particularly,C₇₋₁₂) aralkyloxy group, a herocyclic oxy group, a C₁₋₆ alkylthio group(the sulfur atom may be oxidized), a C₃₋₁₀ (particularly, C₃₋₆)cycloalkylthio group (the sulfur atom may be oxidized), a C₆₋₁₀ arylthiogroup (the sulfur atom may be oxidized), a C₇₋₁₉ (particularly, C₇₋₁₂)aralkyloxy group (the sulfur atom may be oxidized), a herocyclic thiogroup, a herocyclic sulfinyl group, a herocyclic sulfonyl group, a nitrogroup, a halogen atom, a cyano group, a carboxyl group, a C₁₋₁₀(particularly, C₁₋₆) alkoxy-carbonyl group, a C₃₋₆cycloalkyloxy-carbonyl group, a C₆₋₁₀ aryloxy-carbonyl group, a C₇₋₁₉(particularly, C₇₋₁₂) aralkyloxy-carbonyl group, a herocyclicoxycarbonyl group, a C₆₋₁₀ aryl-carbonyl group, C₁₋₆ alkanoyl group,C₃₋₅ alkenoyl group, a C₆₋₁₀ aryl-carbonyloxy group, a C₂₋₆ alkanoyloxygroup, a C₃₋₅ alkenoyloxy group, a carbamoyl group optionally havingsubstituents, a thiocarbamoyl group optionally having substituents, acarbamoyloxy group optionally having substituents, a C₁₋₆ arkanoylaminogroup, a C₆₋₁₀ aryl-carbonylamino group, a C₁₋₁₀ (particularly, C₁₋₆)alkoxy-carboxamide group, a C₆₋₁₀ aryloxy-carboxamide group, a C₇₋₁₉(particularly, C₇₋₁₂) aralkyloxy-carboxamide group, a C₁₋₁₀(particularly, C₁₋₆) alkoxy-carbonyloxy group, a C₆₋₁₀aryloxy-carbonyloxy group, group, a C₇₋₁₉ (particularly, C₇₋₁₂)aralkyloxy-carbonyloxy group, a C₃₋₁₀ (particularly,C₃₋₆)cycloalkyloxy-carbonyloxy group, an ureido group optionally havingsubstituents, a C₆₋₁₀ aryl group optionally having substituents, etc.are used.

These substituents are substituted at substitutable positions in theabove mentioned “aliphatic hydrocarbon group”, and the substituents arenot limited to one and may be same or different and a few numbers (2 to4).

As the “C₁₋₆ alkoxy group”, for example, a methoxy group, an ethoxygroup, a n-propoxy group, an isopropoxy group, a n-butoxy group, atert-butoxy group, a n-pentyloxy group, a n-hexyloxy group, etc. areused, as the “C₃₋₁₀ cycloalkyloxy group”, for example, a cyclopropyloxygroup, a cyclohexyloxy group, etc. are used, as the “C₆₋₁₀ aryloxygroup”, for example, a phenoxy group, a naphtyloxy group, etc. are used,as the “C₇₋₁₉ aralkyloxy group”, for example, a benzyloxy group, a1-phenylethyloxy group, a 2-phenylethyloxy group, a benzhydryloxy group,a 1-naphthylmethyloxy group, etc. are used, as the “C₁₋₆ alkylthio group(the sulfur atom may be oxidized)”, for example, a methylthio group, anethylthio group, a n-propylthio group, a n-butylthio group, amethylsulfinyl group, a methylsulfonyl group, etc. are used, as the“C₃₋₁₀ cycloalkylthio group (the sulfur atom may be oxidized)”, forexample, a cyclopropylthio group, a cyclohexylthio group, acyclopentylsulfinyl group, a cyclohexylsulfonyl group, etc. are used, asthe “C₆₋₁₀ arylthio group (the sulfur atom may be oxidized)”, forexample, a phenylthio group, a naphthylthio group, a phenylsulfinylgroup, a phenylsulfonyl group, etc. are used, as the “C₉₋₁₉ aralkylthiogroup (the sulfur atom may be oxidized)”, for example, a benzylthiogroup, a phenylethylthio group, a benzhydrylthio group, a benzylsulfinylgroup, a benzylsulfonyl group, etc. are used, as the “halogen atom”, forexample, a fluorine atom, a chlorine atom, a bromine atom, an iodineatom, ets. are used, as the “C₁₋₁₀ alkoxy-carbonyl group”, for example,a methoxycarbonyl group, an ethoxycarbonyl group, a n-propoxycarbonylgroup, an isopropoxycarbonyl group, a n-butoxycarbonyl group, aisobutoxycarbonyl group, a tert-butoxycarbonyl group, etc. are used, asthe “C₃₋₆ cycloalkyloxycarbonyl group”, for example, acyclopropyloxycarbonyl group, a cyclopentyloxycarbonyl group, acyclohexyloxycarbonyl group, a norbonyloxycarbonyl group, etc. are used,as the “C₆₋₁₀ aryloxy-carbonyl group”, for example, a phenoxycarbonylgroup, a naphtyloxycarbonyl group, etc. are used, as the “C₇₋₁₉aralkyl-oxycarbonyl group”, for example, a benzyloxycarbonyl group, abenzhydryloxycarbonyl group, a 2-phenethyloxycarbonyl group, etc. areused, as the “C₆₋₁₀ aryl-carbonyl group”, for example, a benzoyl group,a naphtoyl group, a phenylacetyl group, etc. are used, as the “C₁₋₆alkanoyl group”, for example, a formyl group, an acetyl group, apropionyl group, a butyryl group, a valeryl group, a pivaloyl group,etc. are used, as the “C₃₋₅ alkenoyl group”, for example, an acrynoylgroup, a crotnoyl group, etc. are used, as the “C₆₋₁₀ aryl-carbonyloxygroup”, for example, a benzoyloxy group, a naphtoyloxy group, aphenylacetoxy group, etc. are used, as the “C₂₋₆ alkanoyloxy group”, forexample, an acetoxy group, a propionyloxy group, a butyryloxy group, avaleryloxy group, a pivaloyloxy group, etc. are used, as the “C₃₋₅alkenoyl group”, for example, an acrynoyloxy group, a crotnoyloxy group,etc. are used.

As the “carbamoyl group optionally having substituents” (optionallysubstituted carbamoyl group), for example, a carbamoyl group or acyclicaminocarbonyl group, which may be substituted by 1 or 2substituents selected from C₁₋₄ alkyl (e.g., methyl, ethyl, etc.),phenyl, C₁₋₇ acyl (e.g., acetyl, propionyl, benzoyl, etc.), C₁₋₄alkoxy-phenyl (e.g., methoxyphenyl, etc.), etc. and specifically forexample a carbamoyl group, a N-methylcarbamoyl group, a N-ethylcarbamoylgroup, a N,N-dimethylcarbamoyl group, a N,N-diethylcarbamoyl group, aN-phenylcarbamoyl group, a N-acetylcarbamoyl group, a N-benzoylcarbamoylgroup, a N-(p-methoxyphenyl)carbamoyl group, a 1-pyrrolydinylcarboylgroup, a piperazinocarboyl group, a 1-piperazinylcarboyl group, amorpholinocarbamoyl group, etc. are used.

As the “thiocarbamoyl group optionally having substituents” (optionallysubstituted thiocarbamoyl group), for example, a thiocarbamoyl groupwhich may be substituted by 1 or 2 substituents selected from C₁₋₄ alkyl(e.g., methyl, ethyl, etc.), phenyl, etc. and specifically for example athiocarbamoyl group, a N-methylthiocarbamoyl group, aN-phenylthiocarbamoyl group, etc. are used.

As the “carbamoyloxy group optionally having substituents” (optionallysubstituted carbamoyloxy group), for example, a carbamoyloxy group whichmay be substituted by 1 or 2 substituents selected from C₁₋₄ alkyl(e.g., methyl, ethyl, etc.), phenyl, etc. and specifically for example acarbamoyloxy group, a N-methylcarbamoyloxy group, aN,N-dimethylcarbamoyloxy group, a N-ethylcarbamoyloxy group, aN-phenylcarbamoyloxy group, etc. are used.

As the “C₁₋₆ alkanoylamino group”, for example, an acetoamide group, apropionamide group, a butyroamide group, a valeroamide group, apivaroamide group, etc. are used, as the “C₆₋₁₀ aryl-carbonylaminogroup”, for example, a benzamide group, a naphtoamide group, aphtalimide group, etc. are used, as the “C₁₋₁₀ alkoxy-carboxamidegroup”, for example, a methoxycarboxamide (CH₃OCONH—) group, anethoxycarboxamide group, a tert-butoxycarboxamide group, etc. are used,as the “C₆₋₁₀ aryloxy-carboxamide group”, for example, aphenoxycarboxamide (C₆H₅OCONH—) group, etc. are used, as the “C₇₋₁₀aralkyloxy-carboxamide group”, for example, a benzyloxycarboxamide(C₆H₅CH₂OCONH—) group, a benzhydryloxycarboxamide group, etc. are used,as the “C₁₋₁₀ alkoxy-carbonyloxy group”, for example, amethoxycarbonyloxy group, an ethoxycarbonyloxy group, an-propoxycarbonyloxy group, an isopropoxycarbonyloxy group, an-butoxycarbonyloxy group, a tert-butoxycarbonyloxy group, an-pentyloxycarbonyloxy group, a n-hexyloxycarbonyloxy group, etc. areused, as the etc. are used, as the “C₆₋₁₀ aryloxy-carbonyloxy group”,for example, a phenoxycarbonyloxy group, a naphthyloxycarbonyloxy group,etc. are used, as the “C₇₋₁₉ aralkyloxy-carbonyloxy group”, for example,a benzylnoxycarbonyloxy group, a 1-phenylethyloxycarbonyloxy group, a2-phenylethyloxycarbonyloxy group, a benzhydryloxycarbonyloxy group,etc. are used, and as the “C₃₋₁₀ cycloalkyloxy-carbonyloxy group”, forexample, a cyclopropyloxycarbonyloxy group, a cyclohexyloxycarbonyloxygroup, etc. are used.

As the “ureido group optionally having substituents” (optionallysubstituted ureido group), for example, an ureido group optionallysubstituted by 1 to 3 substituents selected from a C₁₋₄ alkyl group(e.g., a methyl group, an ethyl group, etc.), a phenyl group, etc. areused, and for example an ureido group, a 1-methylureido group, a3-methylureido group, a 3,3-dimethylureido group, a 1,3-dimethylureidogroup, a 3-phenylureido group, etc. used.

When a heterocyclic group, a heterocyclic oxy group, a heterocyclic thiogroup, a heterocyclic sulfinyl group, a hetrosulfonyl group or aheterocyclicoxycarbonyl group is used as the “substituents” of the“aliphatic hydrocarbon group optionally having substituents”, theheterocyclic group represents a group formed by excluding one hydrogenatom which binds to the heterocycle, and it represents, for example, a5- to 8-membered cyclic (preferably 5- to 6-membered cyclic) groupcontaining 1 to a few, preferably 1 to 4 hetero atoms such as a nitrogenatom (optionally oxidized), an oxygen atom, a sulfur atom, etc., or acondensed cyclic group thereof. As these heterocyclic group, forexample, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a1,2,3-triazolyl group, a 1,2,4-triazolyl group, a tetrazolyl group, afuryl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a1,2,3-oxadiazolyl group, a 1,2,4-oxadiazolyl group, a 1,2,5-oxadiazolylgroup, a 1,3,4-oxadiazolyl group, a thiazolyl group, an isothiazolylgroup, a 1,2,3-thiadiazolyl group, a 1,2,4-thiadiazolyl group, a1,2,5-thiadiazolyl group, a 1,3,4-thiadiazolyl group, a pyridyl group, apyridazinyl group, a pyrimidinyl group, a pyrazinyl group, an indolylgroup, a pyranyl group, a thiopyranyl group, a dioxynyl group, adioxolyl group, a quinolyl group, a pyrido[2,3-d]pyrimidinyl group,1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl group, athieno[2,3-d]pyridyl group, a benzpyranyl group, a tetrahydrofurylgroup, a tetrahydropyranyl group, a dioxoranyl group, a dioxanyl group,etc. are used.

These heterocyclic groups may be substituted at possible positions by 1to 3 substituents selected from C₁₋₄ alkyl (e.g., methyl, ethyl, etc.),hydroxy, oxo, C₁₋₄ alkoxy (e.g., methoxy, ethoxy, etc.), etc.

As the “C₆₋₁₀ aryl group” the “C₆₋₁₀ aryl group optionally havingsubstituents” (optionally substituted C₆₋₁₀ aryl group), for example, aphenyl group, a naphthyl group, etc. are used. The C₆₋₁₀ aryl group maybe substituted at a substitutable position by a substituent selectedfrom the those listed as a “substituent” (except for an optionallysubstituted C₆₋₁₀ aryl group) of the “aliphatic hydrocarbon optionallyhaving substituents” (optionally substituted aliphatic hydrocarbongroup)

-   -   described above. Such a substituent is substituted at a        substitutable position in a C₆₋₁₀ aryl group, and the number of        such substituents is not limited to one, and, the same or        different, more than one (2 to 4) substituents may exist.

In the “aliphatic hydrocarbon group optionally having substituents”, thesubstituent together with the aliphatic hydrocarbon group may form anoptionally substituted fused ring group, and as these condensed ringgroups, an indanyl group, a 1,2,3,4-tetrahydronaphthyl group, etc. areused. This condensed ring group may be substituted at a substitutableposition by a substituent selected from the those listed as a“substituent” of the “aliphatic hydrocarbon optionally havingsubstituents” described above. Such a substituent is substituted at asubstitutable position in a fused ring group, and the number of suchsubstituents is not limited to one, and, the same or different, morethan one (2 to 4) substituents may exist.

As R, R¹, R^(1a), R^(1b), R^(1c), for example, a lower alkyl grouphaving 1 to 6 carbon atoms (e.g., a methyl group, an ethyl group, an-propyl group, an isopropyl group, a n-butyl group, an isobutyl group,a t-butoxycarbonylmethyl group, a hydroxyethyl group and the like)optionally having substituents, and of them a methyl group, an ethylgroup, a n-propyl group, an isopropyl group, a n-butyl group, anisobutyl group, etc. are preferably used. Particularly, a methyl group,an ethyl group, a n-propyl group and the like, etc. are preferred, andan ethyl group is preferred particularly.

As R², R^(2a), for example, a hydrogen atom, a lower alkyl group having1 to 6 carbon atoms (e.g., a methyl group, an ethyl group, a n-propylgroup, an isopropyl group, a n-butyl group, an isobutyl group, at-butoxycarbonylmethyl group, a hydroxyethyl group and the like), etc.are preferably used, and a hydrogen atom, a methyl group, etc. arepreferably used and particularly a hydrogen atom, etc. are preferablyused.

As the “aromatic hydrocarbon group” of the “aromatic hydrocarbon groupoptionally having substituents” (optionally substituted aromatichydrocarbon group) represented by R, for example, an aromatichydrocarbon group having 6 to 14 carbon atoms (e.g., a phenyl group, anaphthyl group, a biphenyl group, an anthryl group, an indenyl group andthe like) and the like, and particularly an aryl group having 6 to 10carbon atoms and the like (e.g., phenyl and naphthyl groups) arepreferred and a phenyl group and the like are particularly preferred.

As the “substituent” of the “aromatic hydrocarbon group optionallyhaving substituents” represented by R, for example, a halogen atom(e.g., fluorine, chlorine, bromine, iodine and the like), a lower (C₁₋₄)alkyl group (e.g., a methyl group, an ethyl group, a propyl group, abutyl group and the like), a lower (C₁₋₄) alkoxy group (e.g., a methoxygroup, an ethoxy group, a propoxy group, a butoxy group and the like), alower (C₁₋₄) alkoxycarbonyl group (e.g., a methoxycarbonyl group, anethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl groupand the like), a carboxyl group, a nitro group, a cyano group, ahydroxyl group, an acylamino group (e.g., an alkanoylamino group having1 to 4 carbon atoms such as an acetylamino group, a propyonylaminogroup, a butyrylamino group and the like), a cycloalkyl group having 3to 6 carbon atoms (e.g., a cyclopropyl group, a cyclopentyl group andthe like), an aryl group having 6 to 10 carbon atoms (e.g., a phenylgroup, a naphthyl group, an indenyl group and the like), ahalogeno-lower (C₁₋₄) alkyl group (e.g., a trifluoromethyl group, atrifluoroethyl group and the like), a halogeno-lower (C₁₋₄) alkoxy group(e.g., a trifluoromethoxy group, a 1,1,2,2-tetrafluoroethoxy group, a2,2,3,3,3-pentafluoropropoxy group and the like), a lower (C₁₋₄)alkylthio group (e.g., a methylthio group, an ethylthio group, apropionylthio group and the like), a lower (C₁₋₄) alkylsulfonyl group(e.g., a methanesulfonyl group, an ethanesulfonyl group, apropanesulfonyl group and the like), a lower (C₁₋₄) alkanoyl group(e.g., a formyl group, an acetyl group, a propionyl group and the like),a 5-membered aromatic heterocyclic group (e.g., a 1,2,3-triazolyl group,a 1,2,4-triazolyl group, a tetrazolyl group, a thiazolyl group, anisothiazolyl group, an oxazolyl group, an isooxyazolyl group, athiadiazolyl group, a thienyl group, a furyl group and the like), acarbamoyl group, a lower (C₁₋₄) alkyl-carbamoyl group (e.g., amethylcarbamoyl group, a dimethylcarbamoyl group, a propionylcarbamoylgroup and the like), a lower (C₁₋₄) alkoxy-carbonyl-lower (C₁₋₄)alkyl-carbamoyl group (e.g., a butoxycarbonylmethylcarbamoyl group, anethoxycarbonylmethylcarbamoyl group and the like), a1,3-diacylguanidino-lower (C₁₋₄) alkyl group and the like (e.g.,1,3-diacetylguanidinomethyl, 1,3-bis-t-butoxycarbonylguanidinomethyl andthe like) are used, and a halogen atom (e.g., fluorine, chlorine,bromine, iodine atoms and the like), a lower (C₁₋₄) alkyl group and thelike (e.g., a methyl group, an ethyl group, a propyl group, a butylgroup and the like) are preferably used, and a fluorine atom, a chlorineatom and a methyl group are more preferably used.

These substituents are substituted at substitutable positions in thearomatic hydrocarbon group, and the number of the substituents ispreferably 1 to 5, more preferably 1 to 3, most preferably 1 to 2. Whentwo or more of such substituents are present, they may be the same ordifferent.

The “heterocyclic group” in the “heterocyclic group optionally havingsubstituents” (optionally substituted heterocyclic group) represented byR means a 5- to 8-membered (preferably 5- to 6-membered) ring grouphaving 1 to several, preferably 1 to 4, hetero atoms such as a nitrogenatom (optionally oxidized), an oxygen atom, a sulfur atom and the like,or a condensed ring group thereof. As these heterocyclic group, forexample, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a1,2,3-triazolyl group, a 1,2,4-triazolyl group, a tetrazolyl group, afuryl group, a thienyl group, an oxazolyl group, an isoxazolyl group, a1,2,3-oxadiazolyl group, a 1,2,4-oxadiazolyl group, a 1,2,5-oxadiazolylgroup, a 1,3,4-oxadiazolyl group, a thiazolyl group, an isothiazolylgroup, a 1,2,3-thiadiazolyl group, a 1,2,4-thiadiazolyl group, a1,2,5-thiadiazolyl group, a 1,3,4-thiadiazolyl group, a pyridyl group, apyridazinyl group, a pyrimidinyl group, a pyrazinyl group, an indolylgroup, a pyranyl group, a thiopyranyl group, a dioxynyl group, adioxolyl group, a quinolyl group, a pyrido[2,3-d]pyrimidinyl group,1,5-, 1,6-, 1,7-, 1,8-, 2,6- or 2,7-naphthyridyl group, athieno[2,3-d]pyridyl group, a benzpyranyl group, a tetrahydrofurylgroup, a tetrahydropyranyl group, a dioxoranyl group, a dioxanyl group,etc. are used.

These heterocyclic groups may be substituted at possible positions by 1to 3 substituents selected from C₁₋₄ alkyl (e.g., methyl, ethyl, etc.),hydroxy, oxo, C₁₋₄ alkoxy (e.g., methoxy, ethoxy, etc.), etc.

As the “aromatic hydrocarbon group” of the “aromatic hydrocarbon groupoptionally having substituents” (optionally substituted aromatichydrocarbon group) represented by Ar, Ar^(a), for example, an aromatichydrocarbon group having 6 to 14 carbon atoms (e.g., a phenyl group, anaphthyl group, a biphenyl group, an anthryl group, an indenyl group andthe like) and the like, and particularly an aryl group having 6 to 10carbon atoms and the like (e.g., phenyl and naphthyl groups) arepreferred and a phenyl group and the like are particularly preferred.

As the “substituent” of the “aromatic hydrocarbon group optionallyhaving substituents” represented by Ar, Ar^(a), for example, a halogenatom (e.g., fluorine, chlorine, bromine, iodine and the like), a lower(C₁₋₄) alkyl group (e.g., a methyl group, an ethyl group, a propylgroup, a butyl group and the like), a lower (C₁₋₄) alkoxy group (e.g., amethoxy group, an ethoxy group, a propoxy group, a butoxy group and thelike), a lower (C₁₋₄) alkoxycarbonyl group (e.g., a methoxycarbonylgroup, an ethoxycarbonyl group, a propoxycarbonyl group, abutoxycarbonyl group and the like), a carboxyl group, a nitro group, acyano group, a hydroxyl group, an acylamino group (e.g., analkanoylamino group having 1 to 4 carbon atoms such as an acetylaminogroup, a propyonylamino group, a butyrylamino group and the like), acycloalkyl group having 3 to 6 carbon atoms (e.g., a cyclopropyl group,a cyclopentyl group and the like), an aryl group having 6 to 10 carbonatoms (e.g., a phenyl group, a naphthyl group, an indenyl group and thelike), a halogeno-lower (C₁₋₄) alkyl group (e.g., a trifluoromethylgroup, a trifluoroethyl group and the like), a halogeno-lower (C₁₋₄)alkoxy group (e.g., a trifluoromethoxy group, a1,1,2,2-tetrafluoroethoxy group, a 2,2,3,3,3-pentafluoropropoxy groupand the like), a lower (C₁₋₄) alkylthio group (e.g., a methylthio group,an ethylthio group, a propionylthio group and the like), a lower (C₁₋₄)alkylsulfonyl group (e.g., a methanesulfonyl group, an ethanesulfonylgroup, a propanesulfonyl group and the like), a lower (C₁₋₄) alkanoylgroup (e.g., a formyl group, an acetyl group, a propionyl group and thelike), a 5-membered aromatic heterocyclic group (e.g., a 1,2,3-triazolylgroup, a 1,2,4-triazolyl group, a tetrazolyl group, a thiazolyl group,an isothiazolyl group, an oxazolyl group, an isooxyazolyl group, athiadiazolyl group, a thienyl group, a furyl group and the like), acarbamoyl group, a lower (C₁₋₄) alkyl-carbamoyl group (e.g., amethylcarbamoyl group, a dimethylcarbamoyl group, a propionylcarbamoylgroup and the like), a lower (C₁₋₄) alkoxy-carbonyl-lower (C₁₋₄)alkyl-carbamoyl group (e.g., a butoxycarbonylmethylcarbamoyl group, anethoxycarbonylmethylcarbamoyl group and the like), a1,3-diacylguanidino-lower (C₁₋₄) alkyl group and the like (e.g.,1,3-diacetylguanidinomethyl, 1,3-bis-t-butoxycarbonylguanidinomethyl andthe like) are used, and a halogen atom (e.g., fluorine, chlorine,bromine, iodine atoms and the like), a lower (C₁₋₄) alkyl group and thelike (e.g., a methyl group, an ethyl group, a propyl group, a butylgroup and the like) are preferably used, and a fluorine atom, a chlorineatom and a methyl group are more preferably used.

These substituents are substituted at substitutable positions in thearomatic hydrocarbon group, and the number of the substituents ispreferably 1 to 5, more preferably 1 to 3, most preferably 1 to 2. Whentwo or more of such substituents are present, they may be the same ordifferent.

Typically, as Ar or Ar^(a), for example, a phenyl group, ahalogenophenyl group, a lower (C₁₋₄) alkylphenyl group, a lower (C₁₋₄)alkoxyphenyl group, a lower (C₁₋₄) alkoxycarbonylphenyl group, acarboxylphenyl group, a nitrophenyl group, a cyanophenyl group, ahalogeno-lower (C₁₋₄) alkylphenyl group, a halogeno-lower (C₁₋₄)alkoxyphenyl group, a lower (C₁₋₄) alkanoylphenyl group, a 5-memberedaromatic heterocycle-substituted phenyl group, a lower (C₁₋₄)alkoxy-carbonyl-lower (C₁₋₄) alkyl-carbamoylphenyl group,1,3-diacylguanidino-lower (C₁₋₄) alkylphenyl group, a halogen- and lower(C₁₋₄) alkoxy-substituted phenyl group, a halogen- and lower (C₁₋₄)alkoxycarbonyl-substituted phenyl group, a halogen- andcyano-substituted phenyl group, a halogen- and 5-membered aromaticheterocycle-substituted phenyl group, a halogen- and lower (C₁₋₄)alkoxycarbonyl-lower (C₁₋₄) alkyl-carbamoyl-substituted phenyl group andthe like are used.

As Ar or Ar^(a), a halogenophenyl group, a lower (C₁₋₄) alkylphenylgroup, a halogen- and lower (C₁₋₄) alkoxycarbonyl-substituted phenyl andthe like are preferably used.

As Ar or Ar^(a), a group represented by formula:

wherein R⁴ and R⁵ is the same or different and each represents a halogenatom or a lower alkyl group, and n is an integer of 0 to 2, with one inwhich at least one of R⁴ and R⁵ is a halogen atom being furtherpreferred.

As the halogen atom represented by R⁴ and R⁵, a fluorine atom or achlorine atom is preferred.

As the halogenophenyl group, for example, a 2,3-difluorophenyl group, a2,3-dichlorophenyl group, a 2,4-difluorophenyl group, a2,4-dichlorophenyl group, a 2,5-difluorophenyl group, a2,5-dichlorophenyl group, a 2,6-difluorophenyl group, a2,6-dichlorophenyl group, a 3,4-difluorophenyl group, a3,4-dichlorophenyl group, a 3,5-difluorophenyl group, a3,5-dichlorphenyl group, a 2-fluorophenyl group, a 2-chlorophenyl group,a 3-fluorophenyl group, a 3-chlorophenyl group, a 4-fluorophenyl group,a 4-chlorophenyl group, a 2-fluoro-4-chlorophenyl group, a2-chloro-4-fluorophenyl group, a 4-bromo-2-fluorophenyl group, a2,3,4-trifluorophenyl group, a 2,4,5-trifluorophenyl group, a2,4,6-trifluorohenyl group and the like are used.

As the lower (C₁₋₄) alkylphenyl group, a 2-ethylphenyl group, a2,6-diisopropylphenyl group and the like are preferably used, and as thelower (C₁₋₄) alkoxyphenyl group, for example, a 4-methoxyphenyl groupand the like are preferably used.

As the lower (C₁₋₄) alkoxy-carbonylphenyl group, a2-ethoxycarbonylphenyl group, a 2-methoxycarbonylphenyl group, a4-methoxycarbonylphenyl group and the like are preferably used, and asthe halogeno-lower (C₁₋₄) alkylphenyl group, for example, a2-trifluoromethylphenyl group and the like are preferably used, and asthe halogeno-lower (C₁₋₄) alkoxyphenyl group, a 2-trifluoromethoxyphenylgroup, a 4-(2,2,3,3,3-pentafluoropropoxy)phenyl group and the like arepreferably used.

As the lower (C₁₋₄) alkanoylphenyl group, for example, a 2-acetylphenylgroup and the like are preferably used, and as the 5-membered aromaticheterocycle-substituted phenyl, for example, a4-(2H-1,2,3-triazol-2-yl)phenyl group, a 4-(2H-tetrazol-2-yl)phenylgroup, a 4-(1H-tetrazol-1-yl)phenyl group, a4-(1H-1,2,3-triazol-1-yl)phenyl group and the like are preferably used,and as the lower (C₁₋₄) alkoxy-carbonyl-lower (C₁₋₄)alkyl-carbamoylphenyl group, for example, a4-(N-ethoxycarbonylmethylcarbamoyl) phenyl group and the like arepreferably used, and as the 1,3-diacylguanidino-lower (C₁₋₄) alkylphenylgroup, for example, a 4-(1,3-bis-t-butoxycarbonylguanidinomethyl)phenylgroup and the like are preferably used.

As the phenyl group substituted by halogen and lower (C₁₋₄) alkyl, forexample, a 2-fluoro-4-methylphenyl group, a 2-chloro-4-methylphenylgroup, a 4-fluoro-2-methylphenyl group and the like are preferably used,and as the phenyl group substituted by halogen and lower (C₁₋₄)alkoxycarbonyl, for example, a 2-chloro-4-methoxycarbonylphenyl groupand the like are preferably used, and the phenyl group substituted byhalogen and cyano, for example, a 2-chloro-4-cyanophenyl group and thelike are preferably used, and as the phenyl group substituted by halogenand 5-membered aromatic heterocycle, for example, a2-fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl group and the like arepreferably used, and as the phenyl group substituted by halogen andlower (C₁₋₄) alkoxycarbonyl-lower (C₁₋₄) alky-carbamoyl, for example, a2-chloro-4-(N-t-butoxycarbonylmethylcarbamoyl)phenyl group, a2-chloro-4-(N-ethoxycarbonylmethylcarbamoyl) phenyl group and the likeare preferably used.

More specifically, as Ar or Ar^(a), a phenyl group, a phenyl groupsubstituted with 1 to 3 (particularly 1 to 2) halogen atoms (e.g., a2,3-difluorophenyl group, a 2,3-dichlorophenyl group, a2,4-difluorophenyl group, a 2,4-dichlorophenyl group, a2,5-difluorophenyl group, a 2,5-dichlorophenyl group, a2,6-difluorophenyl group, a 2,6-dichlorophenyl group, a3,4-difluorophenyl group, a 3,4-dichlorophenyl group, a3,5-difluorophenyl group, a 3,5-dichlorophenyl group, a4-bromo-2-fluorophenyl group, a 2-fluorophenyl group, a 2-chlorophenylgroup, a 3-fluorophenyl group, a 3-chlorophenyl group, a 4-fluorophenylgroup, a 4-chlorophenyl group, a 2-fluoro-4-chlorophenyl group, a2-chloro-4-fluorophenyl group, a 2,3,4-trifluorophenyl group, a2,4,5-trifluorophenyl group and the like), a phenyl group substituted byhalogen and lower (C₁₋₄) alkyl (e.g., a 2-chloro-4-methylphenyl group, a4-fluoro-2-methylphenyl group and the like), etc. are preferred. Ofthem, a phenyl group substituted with 1 to 3 (particularly 1 to 2)halogen atoms (e.g., a 2,3-dichlorophenyl group, a 2,4-difluorophenylgroup, a 2,4-dichlorophenyl group, a 2,6-diclorophenyl group, a2-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a2-chloro-4-fluorophenyl group, a 2,4,5-trifluorophenyl group and thelike), a phenyl group substituted by halogen and lower (Cl₄) alkyl(e.g., a 2-chloro-4-methylphenyl group, a 4-fluoro-2-methylphenyl groupand the like), etc. are preferred. Particularly, a 2,4-difluorophenylgroup, a 2-chlorophenyl group, a 2-chloro-4-fluorophenyl group, a2-chloro-4-methylphenyl group and the like are preferred, and a2,4-difluorophenyl group, a 2-chloro-4-fluorophenyl group and the likeare preferred.

In this specification, the ring A¹ represents a cycloalkene optionallysubstituted by 1 to 4 substituents selected from the group consisting of(i) an aliphatic hydrocarbon group optionally having substituents, (ii)an aromatic hydrocarbon group optionally having substituents, (iii) agroup represented by formula OR¹ (wherein R¹ is as defined above) and(iv) a halogen atom and a cycloalkene optionally substituted by 1 to 4substituents selected from the group consisting of (i) an aliphatichydrocarbon group optionally having substituents, (ii) an aromatichydrocarbon group optionally having substituents and (iv) a halogen atomare preferred.

In this specification, the ring A² represents a cycloalkene substitutedby 1 to 4 substituents selected from the group consisting of (i) analiphatic hydrocarbon group optionally having substituents, (ii) anaromatic hydrocarbon group optionally having substituents, (iii) a grouprepresented by formula OR¹ (wherein R¹ is as defined above) and (iv) ahalogen atom, and a cycloalkene substituted by 1 to 4 substituentsselected from the group consisting of (i) an aliphatic hydrocarbon groupoptionally having substituents, (ii) an aromatic hydrocarbon groupoptionally having substituents and (iv) a halogen atom are preferred.

These substituents are substituted on substitutable carbon atoms in aring A¹ or ring A², and when the ring A¹ or A² is substituted by two ormore of such substituents, the substituents may be the same ordifferent. A single carbon atom may be substituted by two substituentsand different carbon atoms may be substituted by two or moresubstituents.

As the “aliphatic hydrocarbon group optionally having substituents” as asubstituent on the ring A¹ and ring A², for example, the samesubstituents as the “aliphatic hydrocarbon group optionally havingsubstituents” represented by R, R¹, R^(1a), R^(1b), R^(1c) describedabove may be used.

As the “aromatic hydrocarbon group optionally having substituents” as asubstituent on the ring A¹ and ring A², for example, the samesubstiuents as the “aromatic hydrocarbon group optionally havingsubstituents” represented by Ar or Ar^(a) described above may be used.

As the “heterocyclic group optionally having substituents” as asubstituent on the ring A¹ and ring A², for example, the samesubstiuents as the “heterocyclic group” which is a substituent on the“aliphatic hydrocarbon group optionally having substituents” representedby R, R¹, R^(1a), R^(1b), R^(1c).

As the substituents for the ring A¹ and ring A², 1 or 2 C₁₋₆ alkyl group(e.g., a C₁₋₄ alkyl group such as a methyl group, a tert-butyl group,etc.), a phenyl group, a halogen atom (e.g., fluorine, chlorine,bromine, iodine, etc.), etc. are preferably used.

The group represented by the formula:

wherein n represents the same meaning as defined above, can be a grouprepresented by the formula:

wherein n represents the same meaning as defined above, and preferably agroup represented by the formula:

The group represented by the formula:

wherein n represents the same meaning as defined above, can be a grouprepresented by the formula:

wherein n represents the same meaning as defined above, and preferably agroup represented by the formula:

And, the group represented by the formula:

can be a group represented by the formula:

and preferably a group represented by the formula:

As the integer of 1 to 4 represented by n, 1 to 3 is preferred and 2 ismore preferred.

As the compound represented by the formula (Iaa), the compoundrepresented by the formula (Ibb) is preferred, and as the compoundrepresented by the formula (Ia), the compound represented by the formula(Ib) is preferred.

As the compound represented by the formula (Ibb), the compoundrepresented by the formula (Inn) is preferred, and as the compoundrepresented by the formula (Ib), the compound represented by the formula(In) is preferred.

As the compound (Ibb), (Ib), a compound wherein R¹ is a lower alkylgroup optionally having substituents, R² is a hydrogen atom or a loweralkyl group, Ar is a phenyl group optionally having substituents, n is1, 2 or 3 is preferred, and a compound wherein R¹ is a lower alkyl groupoptionally having substituents, R² is a hydrogen atom, Ar is a phenylgroup substituted by a halogen atom, n is 2 is more preferred,

As the compound represented by the formula (Icc), (Ic), a compoundwherein Ar is a phenyl group optionally having substituents, n is 2 ispreferred.

As the leaving group represented by X¹, for example, a halogen atom(e.g., chlorine, bromine, iodine, etc.), etc. are preferred and achlorine atom is more preferred.

When the compounds represented by formulae (I), (Iaa), (Ibb), (Icc),(Ia), (Ib), (Ic), (Id), (Ie), (If) and (Ig) have stereoisomers, any ofsuch stereoisomers and mixtures thereof are included in the invention.

When a compound represented by formula (Iaa) is a compound representedby formula (Icc) or (Inn), when a compound represented by formula (Ia)is a compound represented by formula (Ic) or (In), when a compoundrepresented by formula (Ie) is a compound represented by formula (Ik) or(Ip), when a compound represented by formula (Id) is a compoundrepresented by formula (Ir), and when a compound represented by formula(Ig) is a compound represented by formula (It), then each compound canexist as an optical isomer with regard to the asymmetric carbon atom ina cycloalkene or cyclohexene ring, and any of such optical isomers andmixtures thereof are included in the invention.

A compound represented by formula (I) or (Ia) may preferably be d-ethyl6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, ethyl6-[N-(2-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, ethyl6-[N-(2-chloro-4-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate ord-ethyl6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate aswell as a salt thereof.

The compounds (I), (Iaa), (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig),(Ibb) and (Icc) (hereinafter simply referred to as an inventiveCompound) may, for example, be converted into a salt with an inorganicbase, organic base, inorganic acid, organic acid, basic or acidic aminoacid. A salt with an inorganic base may, for example, be an alkalinemetal salt such as sodium and potassium salts, an alkaline earth metalsalt such as calcium and magnesium salts, aluminum and ammonium salts,and a salt with an organic base may, for example, be a salt withtrimethylamine, triethylamine, pyridine, picoline, ethanolamine,diethanolamine, triethanolamine, dicyclohexylamine orN,N′-dibenzylethylenediamine. A salt with an inorganic acid may, forexample, be a salt with hydrochloric acid, hydrobromic acid, nitricacid, sulfuric acid or phosphoric acid, and a salt with an organic acidmay, for example, be a salt with formic acid, acetic acid,trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleicacid, citric acid, succinic acid, malic acid, methanesulfonic acid,benzenesulfonic acid or p-toluenesulfonic acid. A salt with a basicamino acid may, for example, be a salt with arginine, lysine orornithine, and a salt with acidic amino acid may, for example, be a saltwith aspartic acid or glutamic acid.

A prodrug for an inventive Compound or a salt thereof is a compoundwhich is converted into an inventive Compound under a physiologicalcondition as a result of a reaction with an enzyme or gastric acid, thusa compound undergoing an enzymatic oxidation, reduction or hydrolyzationto form an inventive Compound and a compound hydrolyzed by gastric acidto form an inventive Compound. A prodrug for an inventive Compound may,for example, be a compound obtained by subjecting an amino group in aninventive Compound to an acylation, alkylation or phosphorylation (e.g.,a compound obtained by subjecting an amino group in an inventiveCompound to an eicosanoylation, alanylation, pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation); a compound obtained by subjecting a hydroxy groupin an inventive Compound to an acylation, alkylation, phosphorylationand boration (e.g., a compound obtained by subjecting a hydroxy group inan inventive Compound to an acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation anddimethylaminomethylcarbonylation); a compound obtained by subjecting acarboxyl group in an inventive Compound to an esterification oramidation (e.g, a compound obtained by subjecting a carboxyl group in aninventive Compound to an ethylesterification, phenylesterification,carboxymethylesterification, dimethylaminomethylesterification,pivaloyloxymethylesterification, ethoxycarbonyloxyethylesterification,phthalidylesterification,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification,cyclohexyloxycarbonylethylesterification and methylamidation) and thelike. Any of these and other precursor or derivative compounds can beproduced from the inventive Compound.

A prodrug for an inventive Compound may also be one which is convertedinto an inventive Compound under a physiological condition, such asthose described in “IYAKUHIN no KAIHATSU (Development ofPharmaceuticals)”, Vol.7, Design of Molecules, p. 163-198, Published byHIROKAWA SHOTEN (1990).

The inventive Compound, a salt thereof and a prodrug therefor can beproduced according to a method known per se, for example, a productionmethod described in WO99/46242 or a method analogous thereto.

The inventive Compound, a salt thereof and a prodrug therefor may be ahydrate or non-hydrate.

The inventive Compound, a salt thereof and a prodrug therefor may belabeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S, ¹²⁵I etc.) and the like.

According to the composition of the present invention, the inventiveCompound, a salt thereof and a prodrug therefor having poor watersolubility can be used effectively as a component of the compositionconstituted by an emulsifier.

The inventive Compound, a salt thereof and a prodrug therefor may existin a state of a liquid or solid in an oil phase, and the composition ofthe present invention is an oil-in-water (O/W type) or S/O/W typeemulsion composition.

The composition of the present invention can be produced using ananionic synthetic phospholipid and a naturally-occurring phospholipid.

The composition of the present invention consists of disperse phaseparticles containing an anionic synthetic phospholipid, anaturally-occurring phospholipid, an oil component and the inventiveCompound, a salt thereof or a prodrug therefor, and water in which thedisperse phase particles are dispersed.

As the anionic synthetic phospholipid, an anionic phospholipid whereintwo chain hydrocarbon groups in a phospholipid molecule is constitutedby a single molecule consisting of one or two kinds of fatty acids, andthe like are used. An anionic synthetic phospholipid of the invention ischaracterized as a mostly homogeneous population of anionic phospholipidmolecules having two hydrocarbon chains. The two hydrocarbon chains ofthe anionic phospholipid molecules are hydrocarbon chains (ie. fattyacids) that may be the same or different species of hydrocarbon chain.Each anionic phospholipid molecule may have two of the same fatty acidchains, or two different fatty acid chains. In the case of a syntheticanionic phospholipid of the invention with each phospholipid moleculehaving two different fatty acid chains, the order of chains proximal tothe phosphate bound carbon is not critical and can vary within thepopulation of mostly homogeneous molecules.

Specific examples of the anionic synthetic phospholipid include a groupof the formula

wherein R⁶ and R⁷ are the same or different and each is a C₇₋₂₀ chainhydrocarbon group, and R⁸ is

or a salt thereof and the like can be used.

The C₇₋₂₀ chain hydrocarbon group represented by R⁶ and R⁷ may be, forexample, C₇₋₂₀ alkyl group, C₇₋₂₀ alkenyl group and the like, and C₇₋₂₀alkyl group is particularly preferable. Furthermore, C₁₀₋₂₀ alkyl groupis preferable, and particularly C₁₂₋₁₈ alkyl group is preferable.

As the anionic synthetic phospholipid, a group of the formula

wherein m is an integer of 7-20, and R⁸ is

is preferable.

The m is preferably an integer of 10-20, and is particularly preferablyan integer of 12-18.

The compounds (II) and (III) can be converted to a salt with aninorganic base, a salt with an organic base, a salt with a basic aminoacid and the like. A salt with an inorganic base may, for example, be analkaline metal salt such as sodium and potassium salts, an alkalineearth metal salt such as calcium and magnesium salts, aluminum andammonium salts, and a salt with an organic base may, for example, be asalt with trimethylamine, triethylamine, pyridine, picoline,ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine orN,N′-dibenzylethylenediamine. A salt with a basic amino acid may, forexample, be a salt with arginine, lysine or ornitine. Of these, alkalimetal salts such as sodium salt are particularly preferable.

More specifically, the anionic synthetic phospholipid may be, forexample, an anionic synthetic phospholipid such asdimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol,distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol,oleoylpalmitoylphosphatidylglycerol, dioctanoylphosphatidic acid,didecanoylphosphatidic acid, dilauroylphosphatidic acid,dimyristoylphosphatidic acid, dipalmitoylphosphatidic acid,diheptadecanoylphosphatidic acid, distearoylphosphatidic acid,dioleoylphosphatidic acid, arachidonylstearoylphosphatidic acid,dipalmitoylphosphatidylserine, dioleoylphosphatidylserine,dimyristoylphosphatidylinositol, dipalmitoylphosphatidylinositol,distearoylphosphatidylinositol, dioleoylphosphatidylinositol,dimyristoylphosphatidylserine, distearoylphosphatidylserine and thelike, particularly preferably dimyristoylphosphatidylglycerol.

The anionic synthetic phospholipid can be used alone or as a mixture oftwo or more kinds thereof.

These anionic synthetic phospholipids can be chemically synthesizedaccording to a method known per se or may be obtained by purification.It is also possible to use a commercially available anionic syntheticphospholipid.

The naturally-occurring phospholipid is a phospholipid mixturecontaining a pluralality (for example, two or more kinds) of molecularspecies depending on the composition of the fatty acid constituting thefatty acid ester. Naturally-occurring phospholipid is a heterogeneousmixture of phospholipids containing two or more molecular species ofphospholipid as distinguished by the fatty ester component of therespective fatty acid chains.

Specifically, as the naturally-occurring phospholipid, for example,phospholipid obtained from natural products by purification, extractionand the like (e.g., non-anionic phospholipids such as egg yolk lecithin,soybean lecithin, phosphatidylcholine and the like), a hydrogenationcomposition of these and the like are used, preferably egg yolklecithin. Particularly preferred is purified egg yolk lecithin capableof intravenous administration, which is described in the pharmaceuticalproduct additive standard and the like.

It is also possible to use a non-ionic surfactant as an emulsifierinstead of the naturally-occurring phospholipid or along with thenaturally-occurring phospholipid.

The non-ionic surfactant is exemplified by polymer surfactants having amolecular weight of about 800-20000, such aspolyoxyethylene-polyoxypropylene copolymer, polyoxyethylene alkyl ether,polyoxyethylene alkyl aryl ether, hydrogenated castor oilpolyoxyethylenederivative, polyoxyethylene sorbitan derivative, polyoxyethylenesorbitol derivative, polyoxyethylene alkyl ether sulfate and the like.

The naturally-occurring phospholipid and the non-ionic surfactant as anemulsifier can be used singly or in combination.

The composition of the present invention contains an anionic syntheticphospholipid in a proportion of about 0.0001-about 5%(W/V), preferablyabout 0.2%(W/V), of the entire composition. More specifically, theamount of the anionic synthetic phospholipid is desirably set to fallwithin the following ranges.

(1) approximately about 0.0001-about 5% (W/V)

(2) approximately about 0.0001-about 2% (W/V)

(3) approximately about 0.0001-about 0.5% (W/V)

(4) approximately about 0.0001-about 0.2% (W/V),

(5) approximately about 0.0001-0.17% (W/V)

(6) approximately about 0.0001-0.15% (W/V)

(7) approximately about 0.0001-0.125% (W/V)

(8) approximately about 0.0001-0.1% (W/V)

(9) approximately about 0.0001-less than about 0.02% (w/v)) (preferably0.0001-0.09% (W/V))

(10) approximately about 0.0001-about 0.08%(W/V)

(11) approximately about 0.0001-about 0.07%(W/V)

(12) approximately about 0.0001-about 0.05%(W/V)

(13) approximately about 0.0001-about 0.03%(W/V)

(14) approximately about 0.0001-about 0.02%(W/V)

(15) approximately about 0.0001-less than about 0.02% (W/V) (preferably0.001-0.019% (W/V))

(16) approximately about 0.0001-0.015% (W/V)

(17) approximately about 0.0001-0.01% (W/V)

(18) approximately about 0.0001-0.009% (W/V)

(19) approximately about 0.0001-0.007% (W/V)

(20) approximately about 0.0001-0.005% (W/V)

(21) approximately about 0.0001-0.003% (W/V)

(22) approximately about 0.0001-0.001% (W/V)

In the above-mentioned (1)-(22), the lower limit may be set to not lessthan about 0.0005%, and in the above-mentioned (1)-(21), the lower limitmay be set to not less than about 0.001%.

It is also possible to use the anionic synthetic phospholipid in aproportion of not less than about 5% (W/V) (for example, about 5-about10%(W/V)), relative to the entire composition of the present invention.

The composition of the present invention contains a naturally-occurringphospholipid in a proportion of generally about 0.1-about 10% (W/V),preferably about 0.2-about 7% (W/V), more preferably about 0.5-about 5%(W/V), relative to the entire composition.

When a non-ionic surfactant is used as an emulsifier, the total amountof the naturally-occurring phospholipid and the non-ionic surfactantrelative to the entire composition of the present invention is generallyabout 0.1-about 10% (W/V), preferably about 0.2-about 7% (W/V), morepreferably about 0.5-about 5% (W/V).

In the composition of the present invention, the proportion of the totalamount of the anionic synthetic phospholipid, naturally-occurringphospholipid and the non-ionic surfactant (hereinafter sometimes to bebriefly referred to as an emulsifier) relative to the oil component is,for example, about 0.1-about 150 wt %, preferably about 0.5-about 125 wt%, more preferably about 1-about 100 wt %. The emulsifier is often usedin a proportion of generally about 1-about 15 wt %, particularly about1-about 10 wt %, relative to the an oil component.

By specifying the amounts of the anionic synthetic phospholipid and thenaturally-occurring phospholipid to be used, the stability of theinventive Compound, a salt thereof and a prodrug therefor, and thecomposition of the present invention can be further improved.

As the oil component, any pharmaceutically acceptable fats and oilsgenerally used for the preparation of fat emulsion in the field ofpharmaceutical technology. Examples of the fats and oils includevegetable oil, fats and oils obtainable by partial hydrogenation ofvegetable oils, oils obtainable by transesterification (simpleglycerides and mixed glycerides), and glycerol esters of medium chainfatty acids.

The aforementioned fats and oils include, for example, a glycerol esterof a fatty acid having about 6 to 30 carbon atoms, preferably about 6 to22 carbon atoms. Examples of the aforementioned fatty acid includesaturated fatty acids such as caproic acid, caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid, stearic acid, behenic acidand the like; unsaturated fatty acids such as palmitooleic acid, oleicacid, linoleic acid, arachidonic acid, icosapentaenoic acid,docosahexaenoic acid and the like.

Preferred examples of the oil component include vegetable oils such assoybean oil, cottonseed oil, rapeseed oil, peanut oil, safflower oil,sesame oil, rice bran oil, corn germ oil, sunflower oil, poppy oil,olive oil and the like. Of these vegetable oils, soybean oil and thelike are preferably used. Particularly preferably, soybean oil that canbe administered intravenously and described in Japan Pharmacopoeia, USP,EP, BP and the like is used.

As the fats and oils, triglyceride of a medium chain fatty acid havingabout 6 to 14 carbon atoms, preferably about 8 to 12 carbon atoms, canbe also used. Preferable glycerine ester of a medium chain fatty acidis, for example, “Migriol 810” and “Migriol 812” (both trade names,manufactured by Huls Co., Ltd., available from Mitsuba Trading Co.,Ltd.), a glyceryl tricaprylate (tricaprylin) such as “Panasate 800”(trade name, manufactured by NOF Corporation, Japan, and the ike.

The composition of the present invention contains an oil component in aproportion of, for example, about 1 to about 30 wt % by weight,preferably about 2 to about 25 wt %, and more preferably about 2.5 toabout 22.5 wt %, of the entire composition.

The composition of the present invention can be prepared by mixing adisperse phase consisting of the inventive Compound, a salt thereof anda prodrug therefor (main drug), the oil component and emulsier, andwater. Where necessary, a stabilizer for improving the stability of theaforementioned main drug, an isotonic agent for adjusting the osmoticpressure, an emulsifying-auxiliaries to enhance emulsifying capability,an emulsification stabilizer for enhancing the stability of theemulsifier and the like may be added.

Examples of the stabilizer include, for example, antioxidants (forexample, ascorbic acid, tocopherol, sorbic acid, retinol and the like),chelating agents (for example, citric acid, tartaric acid and the like)and the like. The stabilizer is used in an amount of generally about0.00001-about 10% (W/V), preferably about 0.0001-about 5% (W/V),relative to the entire composition of the present invention.

The isotonic agent includes, for example, glycerol, sugar alcohols,monosaccharides, disaccharides, amino acid, dextran, albumin and thelike. These isotonic agents may be use singly or in combination.

Examples of the emulsifying-auxiliaries include fatty acids having about6 to 30 carbon atoms, salts of these fatty acids, monoglycerides of thefatty acids. Examples of the aforementioned fatty acid include caproicacid, caprylic acid, capric acid, lauric acid, myristic acid, palmiticacid, stearic acid, behenic acid, palmitooleic acid, oleic acid, linolicacid, arachidonic acid, icosapentaenoic acid, docosahexaenoic acid andthe like. Examples of the salts of include alkali metal salts such assodium salt and potassium salt, calcium salt and the like.

Examples of the emulsifying stabilizer include cholesterol, cholesterolesters, tocopherol, albumin, fatty acid amide derivatives,polysaccharides, derivatives of fatty acid esters of polysaccharides andthe like.

The concentration of the inventive Compound, a salt thereof or a prodrugtherefor in the composition of the present invention varies depending onthe pharmacological activities or kinetics in blood of the compound, andis usually about 0.001-about 5% (W/V), preferably about 0.01-about 2%(W/V), more preferably about 0.1-about 0.5% (W/V). It is also possibleto set the content of the inventive Compound, a salt thereof or aprodrug therefor in the composition of the present invention to about1-about 5000 mg, preferably about 10-about 2000 mg, more preferablyabout 100-about 1000 mg, per 100 ml of the composition. Furthermore, thecontent of the inventive Compound, a salt thereof or a prodrug thereforin the composition of the present invention can be adjusted to about0.001-about 95 wt %, preferably about 0.01-about 30 wt %, morepreferably about 0.1-about 3 wt %, based on the total volume of thecomposition.

The proportion (wt %) of the inventive Compound, a salt thereof or aprodrug therefor relative to the disperse phase comprising an oilcomponent and an emulsifier is generally about 0.0047-about 24%,preferably about 0.047-about 9.4%, more preferably about 0.47-about2.4%.

The composition of the present invention is adjusted to have a pH of notmore than about 6, more specifically about 3-about 6, preferably about3-about 5.5, more preferably about 3-about 5, still more preferablyabout 3-about 4.5.

The pH adjusting agent is exemplified by phosphoric acid, carbonic acid,citric acid, hydrochloric acid, sodium hydroxide and the like, withparticular preference given to hydrochloric acid, sodium hydroxide andthe like.

The composition of the present invention is preferably used as, forexample, an injectable composition.

The composition of the present invention can be produced principallyaccording to a known method or a method analogous thereto. Theemulsification can be conducted in a conventional emulsifying technique.It is preferable to disperse or dissolve the inventive Compound, a saltthereof and a prodrug therefor in an oil component beforehand. Forexample, a mixture of (1) a disperse phase containing the oil componentand the emulsifier, and (2) the inventive Compound, a salt thereof and aprodrug therefor is dispersed in water to give a composition consistingof an O/W type or S/O/W type emulsion.

Preferred examples of the method include a method comprisinghomogenizing a heterogeneous mixture containing a mixture of the maindrug, an oil component, an emulsifier, and where necessary, an additivesuch as an isotonic agent and the like and water in the aforementionedemulsifying apparatus to give a roughly emulsified emulsion, followedby, if necessary, adding water, further homogenizing the resultant roughemulsion using an emulsifying apparatus and removing large particles bya filtering means such as a filter and the like to give an oil-in-watercomposition. The aforementioned mixture is generally heated to, forexample, about 30-about 90° C., preferably about 40-about 80° C. todissolve or disperse the main drug. Examples of the emulsifyingapparatus for the emulsification of the heterogeneous mixture containingthe aforementioned mixture and water include a conventional apparatussuch as a homogenizer including a pressure jetting homogenizer, anultrasonic homogenizer and the like, and a homomixer such as a high-ratemixer and the like. For removing large particles having a particle sizeof not less than about 5 μm, preferably not less than about 1 μm, morepreferably not less than about 0.5 μm, the homogenized emulsion isfrequently subjected to a filtering means such as a filter.

In the composition of the present invention, the mean particle size ofthe disperse phase wherein the inventive Compound, a salt thereof or aprodrug therefor is dissolved, is, for example, mostly about 0.01-about5 μm (about 10-about 5000 nm), preferably about 0.02-about 1 μm (about20-about 1000 nm), more preferably about 0.03-about 0.5 μm (about30-about 500 nm).

In view of the stability of the composition of the present invention andbiodistribution after administration, the mean particle size in thedisperse phase wherein the inventive Compound, a salt thereof or aprodrug therefor is dissolved, is, for example, about 25-about 500 nm,preferably about 50-about 300 nm, more preferably about 100-about 300 nm(particularly about 150-about 260 nm).

A pyrogen can be removed from the composition of the present inventionaccording to a method known per se.

The composition of the present invention is subjected to nitrogen gasdisplacement, sterilized and sealed as necessary.

Since the composition of the present invention has a pH adjusted to notmore than about 6, the inventive Compound, a salt thereof and a prodrugtherefor, as well as the composition of the present invention showsuperior stability even after sterilization in an autoclave etc.Particularly, because the composition of the present invention containsthe anionic synthetic phospholipid and the naturally-occurringphospholipid in specific proportions, more superior stability can bemaintained.

In the composition of the present invention, moreover, the concentrationof the inventive Compound, a salt thereof and a prodrug therefor can beincreased. By controlling the particle size of the disperse phaseparticle, retentivity in blood, blood vessel permeability and migrationperformance into inflammatory site can be enhanced. Therefore, thepharmacokinetics and biodistribution of the inventive Compound, a saltthereof and a prodrug therefor can be improved, thereby enablingtargeting, which in turn leads to more effective administration of adrug with less side effect. Thus, the composition of the presentinvention is useful for the treatment of target disease particularly byan intravenous administration.

Since an inventive Compound, a salt thereof and a prodrug therefor havelow toxicity, an nitric oxide (NO) production-inhibiting effect and aninhibitory effect on the production of an inflammatory cytokine such asTNF-α, IL-1 and IL-6, the composition of the present invention, whichcontains the inventive Compound, a salt thereof or a prodrug therefor isuseful as a therapeutic and/or prophylactic agent in a mammal (e.g.,cat, cattle, dog, horse, goat, monkey, human and the like) against heartdisease, autoimmune disease, inflammatory disease, central nervoussystem disease, infectious disease, sepsis, septic shock and the like,including ichorrhemia, endotoxin shock, exotoxin shock, cardiacdeficiency, shock, hypotension, rheumatoid arthritis, osteoarthritis,gastritis, ulcerative colitis, peptic ulcer, stress-induced gastriculcer, Crohn's disease, autoimmune disease, post-transplant tissuefailure and rejection, postischemic re-perfusion failure, acute coronarymicrovascular embolism, shock-induced vascular embolism (disseminatedintravascular coagulation (DIC) and the like), ischemic cerebraldisorder, arterial sclerosis, malignant anemia, Fanconi's anemia,drepanocythemia, pancreatitis, nephrose syndrome, nephritis, renalfailure, insulin-dependent diabetes, insulin-independent diabetes,hepatic porphyria, alcoholism, Parkinson's disease, chronic leukemia,acute leukemia, tumor, myeloma, side effects of anticancer agents,infantile and adult respiratory distress syndrome, pulmonary emphysema,dementia, Alzheimer's disease, multiple sclerosis, vitamin E deficiency,aging, sunburn, muscular dystrophy, myocarditis, cardiomyopathy,myocardial infarction, sequela of myocardial infaction, osteoporosis,pneumonia, hepatitis, psoriasis, pain, cataract, influenza infection,malaria, human immunodeficiency virus (HIV) infection, radiation-inducedfailure, burn, in vitro fertilization efficiency, hypercalcemia, tonicspondylitis, osteopenia, bone Behcet's disease, osteomalacia, fracture,acute bacterial meningitis, Helicobactor pylori infection, invasivestaphylococcal infection, tuberculosis, systemic mycosis, herpes simplexvirus infection, varicella-helpes zoster virus infection, humanpapilloma virus infection, acute viral encephalitis, encephalitis,asthma, atopic dermatitis, allergic rhinitis, reflux esophargitis,fever, hyper cholesteremia, hyperglycemia, hyperlipidemia, diabeticcomplication, diabetic renal disease, diabetic neuropathy, diabeticretinopathy, gout, gastric atony, hemorrhoid, systemic lupuserythematosus, spinal damage, insomnia, schizophrenia, epilepsy,cirrhosis, hepatic failure, instable angina, valvular disease,dialysis-induced thrombocytopenia, acute ischemic cerebral apoplexy,acute cerebral thrombosis, cancer metastasis, urinary bladder cancer,mammary cancer, uterine cervical cancer, colon cancer, gastric cancer,ovarian cancer, prostatic cancer, parvicellular pulmonary cancer,non-parvicellular pulmonary cancer, malignant melanoma, Hodgkin'sdisease, non-Hodgkin lymphoma and the like.

While the dose of the composition of the present invention may varydepending on the kind of the inventive Compound, age, body weight andcondition, the dosage form, the mode and the period of the treatment, itmay, for example, be generally about 0.01 to about 1000 mg/kg,preferably about 0.01 to about 100 mg/kg, more preferably about 0.1 toabout 100 mg/kg, most preferably about 0.1 to about 50 mg/kg, andparticularly about 1.5 to about 30 mg/kg, as the inventive Compound(Iaa) or (Ie), per day in a patient having a sepsis (adult weighingabout 60 kg), said daily dose being given intravenously all at once orin several portions during a day. It is a matter of course that a lowerdaily dose may be sufficient or an excessive dose may be required sincethe dose may vary depending on various factors as discussed above.

The composition of the present invention can be used concurrently with adrug other than compound (I), a salt thereof and a prodrug therefor.

The drugs that can be used concurrently with the composition of thepresent invention (hereinafter sometimes to be briefly referred to as acombination drug) are, for example, antibacterial agent, antifungalagent, non-steroidal antiinflammatory drug, steroid, anticoagulant,platelet aggregation inhibitor, thrombolytic drug, immunomodulator,antiprotozoal, antibiotic, antitussive and expectorant drug, sedative,anesthetic, antiulcer drug, antiarrhythmic, hypotensive diuretic,tranquilizer, antipsychotic, antitumor drug, hypolipidemic drug, musclerelaxant, anticonvulsant, antidepressant, antiallergic drug, cardiac,antiarrhythmic, vasodilator, vasoconstrictor, hypotensive diuretic,antidiabetic drug, antinarcotic, vitamin, vitamin derivative,therapeutic agent for arthritis, antirheumatic, antiasthmatic,therapeutic agent for pollakiuria/anischuria, therapeutic agent foratopic dermatitis, therapeutic agent for allergic rhinitis, hypertensivedrug, endotoxin-antagonist or -antibody, signal transduction inhibitor,inhibitor of inflammatory mediator activity, antibody to inhibitinflammatory mediator activity, inhibitor of anti-inflammatory mediatoractivity, antibody to inhibit anti-inflammatory mediator activity andthe like. Of these, antibacterial agent, antifungal agent, non-steroidalantiinflammatory drug, steroid, anticoagulant and the like arepreferable. Specific examples thereof include the following.

(1) Antibacterial Agent

{circle around (1)} sulfa drug

sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole,salazosulfapyridine, silver sulfadiazine and the like.

{circle around (2)} quinoline antibacterial agent

nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin,ofloxacin, tosufloxacin tosilate, ciprofloxacin hydrochloride,lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.

{circle around (3)} antiphthisic

isoniazid, ethambutol (ethambutol hydrochloride), p-aminosalicylic acid(calcium p-aminosalicylate), pyrazinamide, ethionamide, protionamide,rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and thelike.

{circle around (4)} antiacidfast bacterium drug

diaphenylsulfone, rifampicin and the like.

{circle around (5)} antiviral drug

idoxuridine, aciclovir, vidarabine, ganciclovir and the like.

{circle around (6)} anti-HIV agent

zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate,ritonavir and the like.

{circle around (7)} antispirochetele

{circle around (8)} antibiotic

tetracycline hydrochloride, ampicillin, piperacillin, gentamicin,dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin,sisomicin, tetracycline, oxytetracycline, rolitetracycline, doxycycline,ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin,cephaloridine, cefaclor, cephalexin, cefroxadine, cefadroxil,cefamandole, cefotoam, cefuroxime, cefotiam, cefotiam hexetil,cefuroxime axetil, cefdinir, cefditoren piboxil, ceftazidime,cefpiramide, cefsulodin, cefinenoxime, cefpodoxime proxetil, cefpirome,cefozopran, cefepime, cefsulodin, cefinenoxime, cefinetazole, cefminox,cefoxitin, cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime,cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin,aztreonam or a salt thereof, griseofulvin, lankacidin-group antibiotics(J. Antibiotics, 38, 877-885 (1985)) and the like.

(2) Antifungal Agent

{circle around (1)} polyethylene antibiotic (e.g., amphotericin B,nystatin, trichomycin)

{circle around (2)} griseofulvin, pyrrolnitrin and the like

{circle around (3)} cytosine metabolism antagonist (e.g., flucytosine)

{circle around (4)} imidazole derivative (e.g., econazole, clotrimazole,miconazole nitrate, bifonazole, croconazole)

{circle around (5)} triazole derivative (e.g. fluconazole, itraconazole,azole compound[2-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-3(2H,4H)-1,2,4-triazolone]

{circle around (6)} thiocarbamic acid derivative (e.g. trinaphthol)

{circle around (7)} echinocandin derivative (e.g., caspofungin,micafungin, anidulafungin) and the like.

(3) non-Steroidal Antiinflammatory Drug

acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrin, migrenin,aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofensodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen,oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, epirizole,tiaramide hydrochloride, zaltoprofen, gabexate mesilate, camostatmesilate, urinastatin, colchicine, probenecid, sulfinpyrazone,benzbromarone, allopurinol, gold sodium thiomalate, sodium hyaluronate,sodium salicylate, morphine hydrochloride, salicylic acid, atropine,scopolamine, morphine, pethidine, levorphanol, ketoprofen, naproxen,oxymorphone or a salt thereof, and the like.

(4) Steroid

dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone,triamcinolone acetonide, fluocinonide, fluocinolone acetonide,prednisolone, methylprednisolone, cortisone acetate, hydrocortisone,fluorometholone, beclometasone dipropionate, estriol and the like.

(5) Anticoagulant

heparin sodium, sodium citrate, activated protein C, tissue factorpathway inhibitor, antithrombin III, dalteparin sodium, warfarinpotassium, argatroban, gabexate, sodium citrate and the like.

(6) Platelet Aggregation Inhibitor

ozagrel sodium, ethyl icosapentate, beraprost sodium, alprostadil,ticlopidine hydrochloride, pentoxifylline, dipyridamole and the like.

(7) Thrombolytic Drug

tisokinase, urokinase, streptokinase and the like.

(8) Immunomodulator

cyclosporin, tacrolimus, gusperimus, azathioprine, antilymphocyte serum,dried sulfonated immunoglobulin, erythropoietin, colony-stimulatingfactor, interleukin, interferon and the like.

(9) Antiprotozoal

metronidazole, tinidazole, diethylcarbamazine citrate, quininehydrochloride, quinine sulfate and the like.

(10) Antitussive and Expectorant Drug

ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate,dihydrocodeine phosphate, isoproterenol hydrochloride, ephedrinehydrochloride, methylephedrine hydrochloride, noscapine hydrochloride,alloclamide, chlophedianol, picoperidamine, chloperastine, protokylol,isoproterenol, salbutamol, terbutaline, oxymetabanol, morphinehydrochloride, dextromethorphan hydrobromide, oxycodone hydrochloride,dimemorphan phosphate, tipepidine hibenzate, pentoxyverine citrate,clofedanol hydrochloride, benzonatate, guaifenesin, bromhexinehydrochloride, ambroxol hydrochloride, acetylcysteine, ethyl cysteinehydrochloride, carbocysteine and the like.

(11) Sedative

chlorpromazine hydrochloride, atropine sulfate, phenobarbital, barbital,amobarbital, pentobarbital, thiopental sodium, thiamylal sodium,nitrazepam, estazolam, flurazepam, haloxazolam, triazolam,flunitrazepam, bromovalerylurea, chloral hydrate, triclofos sodium andthe like.

(12) Anesthetic

(12-1) Local Anesthetic

cocaine hydrochloride, procaine hydrochloride, lidocaine, dibucainehydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride,bupivacaine hydrochloride, oxybuprocaine hydrochloride, ethylaminobenzoate, oxethazaine) and the like.

(12-2) General Anesthetic

{circle around (1)} inhalation anesthetic (e.g., ether, halothane,nitrous oxide, isoflurane, enflurane),

{circle around (2)} intravenous anesthetic (e.g., ketaminehydrochloride, droperidol, thiopental sodium, thiamylal sodium,pentobarbital) and the like.

(13) Antiulcer Drug

metoclopromide, histidine hydrochloride, lansoprazole, metoclopramide,pirenzepine, cimetidine, ranitidine, famotidine, urogastrone,oxethazaine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate,gefarnate, aldioxa, teprenone, prostaglandin and the like.

(14) Antiarrhythmic

{circle around (1)} Na channel blocker (e.g., quinidine, procainamide,disopyramide, ajmaline, lidocaine, mexiletine, phenitoin),

{circle around (2)} β-blocker (e.g., propranolol, alprenolol, bufetolol,oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol,carteolol, arotinolol,

{circle around (3)} K channel blocker (e.g., amiodarone),

{circle around (4)} Ca channel blocker (e.g., verapamil, diltiazem) andthe like.

(15) Hypotensive Diuretic

hexamethonium bromide, clonidine hydrochloride, hydrochlorothiazide,trichlormethiazide, furosemide, ethacrynic acid, bumetamide, mefruside,azosemide, spironolactone, potassium canrenoate, triamterene, amiloride,acetazolamide, D-mannitol, isosorbide, aminophyllin and the like.

(16) Tranquilizer

diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam,cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzineand the like.

(17) Antipsychotic

chlorpromazine hydrochloride, prochlorperazine, trifluoperazine,thioridazine hydrochloride, perphenazine maleate, fluphenazineenanthate, prochlorperazine maleate, levomepromazine maleate,promethazine hydrochloride, haloperidol, bromperidol, spiperone,reserpine, clocapramine dihydrochloride, sulpiride, zotepine and thelike.

(18) Antitumor Drug

6-O—(N-chloroacetylcarbamoyl)fumagillol, bleomycin, methotrexate,actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin,cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil,picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin,doxorubicin hydrochloride, aclarubicin hydrochloride, bleomycinhydrochloride, peplomycin sulfate, vincristine sulfate, vinblastinesulfate, irinotecan hydrochloride, cyclophosphamide, melphalan,busulphan, thiotepa, procarbazine hydrochloride, cisplatin,azathioprine, mercaptopurine, tegafur, carmofur, cytarabine,methyltestosterone, testosterone propionate, testosterone enanthate,mepitiostane, fosfestol, chlormadinone acetate, leuprorelin acetate,buserelin acetate and the like.

(19) Hypolipidemic Drug

clofibrate, ethyl2-chloro-3-[4-(2-methyl-2-phenylpropoxy)phenyl]propionate (Chem. Pharm.Bull, 38, 2792-2796 (1990)), pravastatin, simvastatin, probucol,bezafibrate, clinofibrate, nicomol, cholestyramine, dextran sulfatesodium and the like.

(20) Muscle Relaxant

pridinol, tubocurarine, pancuronium, tolperisone hydrochloride,chlorphenesin carbamate, baclofen, chlormezanone, mephenesin,chlorzoxazone, eperisone, tizanidine and the like.

(21) Anticonvulsant

phenyloin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione,carbamazepine, phenobarbital, primidone, sulthiame, sodium valproate,clonazepam, diazepam, nitrazepam and the like.

(22) Antidepressant

imipramine, clomipramine, noxiptiline, phenelzine, amitriptylinehydrochloride, nortriptyline hydrochloride, amoxapine, mianserinhydrochloride, maprotiline hydrochloride, sulpiride, fluvoxaminemaleate, trazodone hydrochloride and the like.

(23) Antiallergic Drug

diphenhydramine, chlorpheniramine, tripelennamine, metodilamine,clemizole, diphenylpyraline, methoxyphenamine, disodium cromoglycate,tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine,mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlkasthydrate, seratrodast and the like.

(24) Cardiac

trans-pi-oxocamphor, terephyllol, aminophyllin, etilefrine, dopamine,dobutamine, denopamine, ubidecarenone aminophyllin, bencirin, amrinone,pimobendan, digitoxin, digoxin, methyldigoxin, lanatoside C,G-strophanthin and the like.

(25) Vasodilator

oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan, clonidine,methyldopa, guanabenz and the like.

(26) Vasoconstrictor

dopamine, dobutamine denopamine and the like.

(27) Hypotensive Diuretic

hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine,diltiazem, nifedipine and the like.

(28) Antidiabetic Drug

tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide,acarbose, epalrestat, troglitazone, glucagon, glymidine, glipzide,phenformin, buformin, metformin and the like.

(29) Antinarcotic

levallorphan, nalorphine, naloxone or a salt thereof and the like.

(30) Fat-Soluble Vitamin

{circle around (1)} vitamin A: vitamin A₁, vitamin A₂ and retinolpalmitate

{circle around (2)} vitamin D: vitamin D₁, D₂, D₃, D₄ and D₅

{circle around (3)} vitamin E: α-tocopherol, β-tocopherol, γ-tocopherol,δ-tocopherol, dl-α-tocopherol nicotinate

{circle around (4)} vitamin K: vitamin K₁, K₂, K₃ and K₄

{circle around (5)} folic acid (vitamin M) and the like.

(31) Vitamin Derivative

various derivatives of vitamins, for example, vitamin D₃ derivativessuch as 5,6-trans-cholecalciferol, 2,5-hydroxycholecalciferol,1-α-hydroxycholecalciferol and the like, vitamin D₂ derivatives such as5,6-trans-ergocalciferol and the like.

(32) Antiasthmatic

isoprenaline hydrochloride, salbutamol sulfate, procaterolhydrochloride, terbutaline sulfate, trimetoquinol hydrochloride,tulobuterol hydrochloride, orciprenaline sulfate, fenoterolhydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropiumbromide, flutropium bromide, theophyline, aminophyllin, disodiumcromoglycate, tranilast, repirinast, anrexanone, ibudilast, ketotifen,terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride,pranlkast hydrate, seratrodast, dexamethasone, prednisolone,hydrocortisone, beclometasone dipropionate and the like.

(33) Therapeutic Agent for Pollakiuria/Anischuria

flavoxate hydrochloride and the like.

(34) Atopic Dermatitis

disodium cromoglycate and the like.

(35) Therapeutic Agent for Allergic Rhinitis

disodium cromoglycate, chlorpheniramine maleate, alimemazine tartrate,clemastine fumarate, homochlorcyclizine hydrochloride, terfenadine,mequitazine and the like;

(36) Hypertensive Drug

dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin,lanatoside C, G-strophanthin and the like.

(37) Others

hydroxicam, diaserine, megestrol acetate, nicerogolin, prostaglandinsand the like.

A combined use of the composition of the present invention and acombination drug provides the following effects.

(1) The dose of the compound (I), a salt thereof and a prodrug thereforcan be reduced than a sole administration of the composition of thepresent invention.

(2) A synergistic therapeutic effect can be achieved against theabove-mentioned sepsis, septic shock, inflammatory diseases, infectiousdiseases and the like.

(3) A broad range of therapeutic effect can be achieved against variousdiseases developed in association with viral infection and the like.

With regard to the use of the composition of the present invention and acombination drug, the composition of the present invention and thecombination drug are free of any limitation on the timing of theadministration or the composition of the present invention, and thecombination drug may be simultaneously administered to theadministration object, or may be administered with time difference. Thedose of the combination drug follows a clinical dose and can beappropriately determined depending on the administration object,administration route, disease, combination and the like.

The mode of administration of the composition of the present inventionand the combination drug is not particularly limited, as long as thecomposition of the present invention and the combination drug arecombined for administration. While the mode of such administrationvaries depending on the kind of the combination drug and the like, forexample, (1) administration of a single preparation obtained bysimultaneous addition of the composition of the present invention andthe combination drug, (2) simultaneous administration of two kinds ofpreparations obtained by separate preparation of the composition of thepresent invention and a pharmaceutical composition of the combinationdrug, by a single administration route, (3) time stagger administrationof two kinds of preparations obtained by separate preparation of thecomposition of the present invention and a pharmaceutical composition ofthe combination drug, by a single administration route, (4) simultaneousadministration of two kinds of preparations obtained by separatepreparation of the composition of the present invention and apharmaceutical composition of the combination drug, by differentadministration routes, (5) time stagger administration of two kinds ofpreparations obtained by separate preparation of the composition of thepresent invention and a pharmaceutical composition of the combinationdrug, by different administration routes, such as administration in theorder of the composition of the present invention and then apharmaceutical composition of the combination drug, or in a reversedorder, and the like are exemplified.

A pharmaceutical composition of the combination drug has low toxicityand can be administered safely by admixing the combination drug with,for example, a pharmacologically acceptable carrier according to amethod known per se to give a pharmaceutical composition, such astablets (inclusive of sugar-coated tablets and film-coated tablets),powders, granules, capsules, (inclusive of soft capsules), liquids,injections, suppositories, sustained release agents and the like, fororal or parenteral (e.g., topical, rectal or intravenous administration)administration. An injection can be administered intravenously,intramuscularly, subcutaneously, into the organs or directly into thelesion.

As the pharmacologically acceptable carrier usable for the production ofthe pharmaceutical composition of a combination drug, there arementioned various conventional organic or inorganic carriers as amaterial for the preparation. Examples thereof include excipients,lubricants, binders and disintegrators for solid preparations, andsolvents, solubilizing aids, suspending agents, isotonic agents, buffersand soothing agents for liquid preparations. Where necessary,conventional additives such as antiseptics, antioxidants, coloringagents, sweeteners, absorbents, moistening agents and the like can beused appropriately in suitable amounts.

As the excipient, there are mentioned, for example, lactose, sucrose,D-mannitol, starch, corn starch, crystalline cellulose, light anhydroussilicic acid and the like.

As the lubricant, there are mentioned, for example, magnesium stearate,calcium stearate, talc, colloidal silica and the like.

As the binder, there are mentioned, for example, crystalline cellulose,saccharose, D-mannitol, dextrin, hydroxypropylcellulose,hydroxypropylmethylcellulose, polyvinylpyrrolidone, starch, sucrose,gelatin, methylcellulose, carboxymethylcellulose sodium and the like.

As the disintegrator, there are mentioned, for example, starch,carboxymethylcellulose, carboxymethylcellulose calcium, sodiumcarboxymethyl starch, L-hydroxypropylcellulose and the like.

As the solvent, there are mentioned, for example, injectable water,alcohol, propylene glycol, Macrogol, sesame oil, corn oil, olive oil andthe like.

As the solubilizing aid, there are mentioned, for example, polyethyleneglycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol,tris-aminomethane, cholesterol, triethanolamine, sodium carbonate,sodium citrate and the like.

As the suspending agent, there are mentioned, for example, surfactantssuch as stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethoniumchloride, glyceryl monostearate and the like; hydrophilic polymers suchas polyvinyl alcohol, polyvinylpyrrolidone, carboxymethylcellulosesodiium, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose and the like.

As the isotonic agent, there are mentioned, for example, glucose,D-sorbitol, sodium chloride, glycerine, D-mannitol and the like.

As the buffer, there are mentioned, for example, buffers such asphosphate, acetate, carbonate, citrate and the like.

As the soothing agent, there are mentioned, for example, benzyl alcoholand the like.

As the antiseptic, there are mentioned, for example, p-oxybenzoates,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid,sorbic acid and the like.

As the antioxidant, there are mentioned, for example, sulfite, ascorbicacid, α-tocopherol and the like.

When a combination drug is added to the composition of the presentinvention, the amount of the combination drug can be appropriatelydetermined depending on the administration object, administration route,disease and the like, and can be adjusted as are the aforementionedcompound (I), a salt thereof and a prodrug therefor.

When the composition of the present invention and a pharmaceuticalcomposition of the combination drug are used in combination, the contentof the combination drug in the pharmaceutical composition of thecombination drug can be appropriately determined depending on theadministration object, administration route, disease and the like. It isgenerally about 0.01-100 wt %, preferably about 0.1-50 wt %, morepreferably about 0.5-20 wt %, based on the preparation in total.

The content of the additive, such as a carrier, in the pharmaceuticalcomposition of the combination drug varies depending on the form of thepreparation. It is generally about 1-99.99 wt %, preferably about 10-90wt %, based on the preparation in total.

A combination drug can be prepared into an aqueous injection togetherwith a dispersant (e.g., Tween 80 (ATLASPOWDER USA), HCO60 (NIKKOCHEMICALS), polyethylene glycol, carboxymethylcellulose, sodiumarginate, hydroxypropylmethylcellulose, dextrin and the like, astabilizing agent (e.g., ascorbic acid, sodium pyrosulfite and thelike), a surfactant (e.g., polysorbate 80, Macrogol and the like), asolubilizing agent (e.g., glycerine, ethanol and the like), a bufferingagent (e.g., phosphoric acid, alkali metal salt thereof, citric acid,alkali metal salt thereof and the like), an isotonic agent (e.g., sodiumchloride, potassium chloride, mannitol, sorbitol, glucose and the like),a pH adjusting agent (hydrochloric acid, sodium hydroxide and the like),a preservative (ethyl p-hydroxybenzoate, benzoic acid, methylparaben,propylparaben, benzyl alcohol and the like), a solubilizer (e.g., conc.glycerine, meglumine and the like), a solubilizing aid (e.g., propyleneglycol, sucrose and the like), a soothing agent (e.g., glucose, benzylalcohol and the like) and the like, or by dissolving, suspending oremulsifying in a vegetable oil (e.g., olive oil, sesame oil, peanut oil,cottonseed oil, corn oil and the like) or a solubilizing aid such aspropylene glycol and the like to form an oil-based injectionformulation.

In addition, a combination drug may be used instead of the compound (I),a salt thereof or a prodrug therefor to give an emulsion composition forinjection of the present invention.

An oral formulation can be produced by compressing a combination drugtogether with an excipient (e.g., lactose, sucrose, starch and thelike), a disintegrant (e.g., starch, calcium carbonate and the like), abinder (e.g., starch, gum arabic, carboxymethyl cellulose, polyvinylpyrrolidone, hydroxypropyl cellulose and the like) or a glidant (e.g.,talc, magnesium stearate, polyethylene glycol 6000 and the like) asappropriate, followed by a coating process known per se for the purposeof masking a taste, forming an enteric coat, or achieving a sustainedrelease. Such coating may, for example, be hydroxypropylmethylcellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pluronic F68, celluloseacetate phthalate, hydroxypropylmethyl cellulose phthalate,hydroxymethyl cellulose acetate succinate, Eudragid (ROHME, Germany, acopolymer of methacrylic acid and acrylic acid), a dye (e.g., colcothar,titanium oxide and the like) as appropriate.

The preparation for oral administration may be either a rapid releasepreparation or a sustained release preparation.

For example, when a suppository is produced, a combination drug may beformulated also as an oil-based or aqueous solid or semi-solid or liquidsuppository by a method known per se. An oil-based suppository base may,for example, be a higher fatty glyceride (e.g., cocoa butter, WITEPSOL(DYNAMIT NOBEL) and the like), a middle fatty acid (e.g., MYGLYOL(DYNAMIT NOBEL) and the like), or a vegetable oil (e.g., sesame oil,soybean oil, cottonseed oil and the like) and the like as appropriate.An aqueous base may, for example, be a polyethylene glycols or apropylene glycol, and an aqueous gel base may, for example, be a naturalgum, a cellulose derivative, a vinyl polymer, an acrylic polymer and thelike.

Examples of the above-mentioned sustained release preparation includesustained release microcapsule and the like.

A sustained release microcapsule can be prepared by a method known perse. For example, a sustained release preparation shown in the following[2] is preferably formed and administered.

A combination drug can be formed into a preparation for oraladministration such as a solid preparation (e.g., powder, granule,tablet, capsule) and the like, or a preparation for rectaladministration such as a suppository and the like, depending on the kindof the drug.

In the following, [1] an injection of the combination drug andpreparation thereof, [2] a sustained release preparation or a rapidrelease preparation of a combination drug and preparation thereof, and[3] a sublingual tablet, buccal or oral cavity rapid disintegrator of acombination drug and preparation thereof are concretely explained.

[1] Injection and Preparation Thereof

An injection containing a combination drug dissolved in water ispreferable. The injection may contain benzoate and/or salicylate.

The injection is obtained by dissolving both a combination drug and,where desired, benzoate and/or salicylate in water.

The salt of the above-mentioned benzoic acid and salicylic acidincludes, for example, alkali metal salts such as sodium, potassium andthe like, alkaline earth metal salts such as calcium, magnesium and thelike, ammonium salt, meglumine salt, and organic acid salt such astromethamol and the like, and the like.

The concentration of the combination drug in the injection is about0.5-50 w/v %, preferably about 3-20 w/v %. The concentration of thebenzoate and/or salicylate is preferably 0.5-50 w/v %, more preferably3-20 w/v %.

The injection may contain additives generally used for injections, suchas a stabilizing agent (e.g., ascorbic acid, sodium pyrosulfite and thelike), a surfactant (e.g., polysorbate 80, Macrogol and the like), asolubilizing agent (e.g., glycerine, ethanol and the like), a bufferingagent (e.g., phosphoric acid, alkali metal salt thereof, citric acid,alkali metal salt thereof and the like), an isotonic agent (e.g., sodiumchloride, potassium chloride and the like), a dispersing agent (e.g.,hydroxypropylmethylcellulose, dextrin), a pH adjusting agent(hydrochloric acid, sodium hydroxide and the like), a preservative(ethyl p-hydroxybenzoate, benzoic acid and the like), a solubilizer(e.g., conc. glycerine, meglumine and the like), a solubilizing aid(e.g., propylene glycol, sucrose and the like), a soothing agent (e.g.,glucose, benzyl alcohol and the like) and the like as appropriate. Theseadditives are added in a proportion generally employed for injections.

The injection is preferably adjusted to pH 2-12, preferably 2.5-8.0, bythe use of a pH adjusting agent.

The injection can be obtained by dissolving both the combination drugand, where desired, benzoate and/or salicylate, and where necessary, theabove-mentioned additives in water. These may be dissolved in any orderin a suitable manner as in conventional production of injections.

The injectable aqueous solution is preferably heated and, in the samemanner as with conventional injections, subjected to, for example,sterilization by filtration, high pressure sterilization by heating andthe like to provide an injection.

The injectable aqueous solution is preferably subjected to high pressuresterilization by heating at, for example, 100° C.-121° C. for 5 min-30min.

It may be prepared into an antibacterial solution, so that it can beused as a preparation for plural subdivided administrations.

[2] Sustained Release Preparation or Rapid Release Preparation andPreparation Thereof

A sustained release preparation wherein a core containing a combinationdrug is covered on demand with a film forming agent, such as awater-insoluble material, a swellable polymer and the like, ispreferable. For example, a sustained release preparation for oraladministration once a day is preferable.

The water-insoluble material to be used for the film forming agent is,for example, cellulose ethers such as ethylcellulose, butylcellulose andthe like; cellulose esters such as cellulose acetate, cellulosepropionate and the like; polyvinyl esters such as poly(vinyl acetate),poly(vinyl butyrate) and the like; acrylic polymers such as acrylicacid/methacrylic acid copolymer, methyl methacrylate copolymer,ethoxyethyl methacrylate/cinnamoethyl methacrylate/aminoalkylmethacrylate copolymer, polyacrylic acid, polymethacrylic acid,methacrylic acid alkylamide copolymer, poly(methyl methacrylate),polymethacrylate, polymethacrylic amide, aminoalkyl methacrylatecopolymer, poly(methacrylic anhydride) and glycidyl methacrylatecopolymer, particularly Eudragits (Rohm Pharma) such as Eudragit RS-100,RL-100, RS-30D, RL-30D, RL-PO, RS-PO (ethyl acrylate.methylmethacrylate.trimethyl chloride methacrylate.ammonium ethyl copolymer),Eudragit NE-30D (methyl methacrylate.ethyl acrylate copolymer) and thelike, and the like; hydrogenated oils such as hydrogenated castor oil(e.g.,

; “Lovely Wax” (Freund Inc.)) and the like) and the like; waxes such ascarnauba wax, fatty acid glycerine ester, paraffin and the like;polyglycerine fatty acid ester and the like.

As the swellable polymer, a polymer having an acidic dissociable group,which shows pH-dependent swelling, is preferable, and a polymer havingan acidic dissociable group, which shows less swelling in an acidicrange, such as in the stomach, but otherwise in a neutral range, such asin the small intestine and large intestine, is preferable.

Examples of the polymer having an acidic dissociable group, which showspH-dependent swelling, include crosslinking type polyacrylic acidpolymers such as Carbomer 934P, 940, 941, 974P, 980, 1342 and the like,polycarbophil, carcium polycarbophil (all mentioned above are theproduct of BF Goodrich), HI-BIS-WAKO 103, 104, 105, 304 (all beingproducts of Waco Pure Chemicals Industries, Ltd.) and the like.

The film forming agent to be used for the sustained release preparationmay further contain a hydrophilic material.

Examples of the hydrophilic material include polysaccharides optionallyhaving a sulfuric acid group such as pullulan, dextrin, alkali metalsalt of alginic acid and the like; polysaccharides having a hydroxyalkyl group or a carboxy alkyl group such as hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose sodium and thelike; methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol,polyethylene glycol and the like.

The content of the water-insoluble material of the film forming agentfor a sustained release preparation is about 30-about 90% (w/w),preferably about 35-about 80% (w/w), more preferably about 40-75% (w/w),and the content of the swellable polymer is about 3-about 30% (w/w),preferably about 3-about 15% (w/w). The film forming agent may furthercontain a hydrophilic material, in which case the content of thehydrophilic material for film forming agent is not more than about 50%(w/w), preferably about 5-about 40% (w/w), more preferably about 5-about35% (w/w). As used herein, the above-mentioned % (w/w) is a percentagerelative to the film forming agent composition wherein the solvent(e.g., water, lower alcohol such as methanol, ethanol and the like) hasbeen removed from the film forming liquid agent.

A sustained release preparation is produced by preparing a corecontaining a drug as exemplarily mentioned below, and coating theresulting core with a film forming liquid agent prepared by dissolvingby heating or dissolving or dispersing in a solvent a water-insolublematerial, a swellable polymer and the like.

I. Preparation of Core Containing a Drug

The form of the core containing a drug (hereinafter sometimes simplyreferred to as a core) to be coated with a film forming agent is notparticularly limited, but it is preferably formed into particles such asgranules, subtilized granules and the like.

When the core is made of granules or subtilized granules, the averageparticle size thereof is preferably about 150-2,000 μm, more preferablyabout 500-about 1,400 μm.

The core can be prepared by a typical production method. For example, adrug is mixed with suitable excipients, binders, disintegrators,lubricants, stabilizers and the like, and subjected to wet extrusiongranulation, fluidized bed granulation and the like.

The drug content of the core is about 0.5-about 95% (w/w), preferablyabout 5.0-about 80% (w/w), more preferably about 30-about 70% (w/w).

Examples of the excipient to be contained in the core includesaccharides such as sucrose, lactose, mannitol, glucose and the like,starch, crystalline cellulose, calcium phosphate, corn starch and thelike. Of these, crystalline cellulose and corn starch are preferable.

Examples of the binder include polyvinyl alcohol,hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone,Pluronic F68, gum arabic, gelatin, starch and the like. Examples of thedisintegrator include carboxymethylcellulose calcium (ECG505),crosscarmelose sodium (Ac-Di-Sol), crosslinked polyvinylpyrrolidone(Crospovidone), low substituted hydroxypropylcellulose (L-HPC) and thelike. Of these, hydroxypropylcellulose, polyvinylpyrrolidone and lowsubstituted hydroxypropylcellulose are preferable. Examples of thelubricant and coagulation preventive include talc, magnesium stearateand inorganic salts thererof, and examples of the lubricant includepolyethylene glycol and the like. Examples of the stabilizer includeacids such as tartaric acid, citric acid, succinic acid, fumaric acidacid, maleic acid and the like.

The core can be also prepared, besides the above-mentioned productionmethods, by, for example, rolling granulation wherein a drug or amixture of a drug and an excipient, a lubricant and the like is added bysmall portions while spraying a binder dissolved in a suitable solventsuch as water, lower alcohol (e.g., methanol, ethanol and the like) andthe like on an inert carrier particles to be the center of the core, apan coating method, a fluidized bed coating method or a melt granulatingmethod. Examples of the inert carrier particle include those preparedfrom sucrose, lactose, starch, crystalline cellulose and waxes, whichpreferably has an average particle size of about 100 μm-about 1,500 μm.

To separate the drug contained in the core from the film forming agent,the surface of the core may be coated with a protective agent. Examplesof the protective agent include the aforementioned hydrophilic material,water-insoluble material and the like. As the protective agent,preferably polyethylene glycol, polysaccharides having a hydroxy alkylgroup or a carboxy alkyl group, more preferablyhydroxypropylmethylcellulose and hydroxypropylcellulose are used. Theprotective agent may contain, as a stabilizer, an acid such as tartaricacid, citric acid, succinic acid, fumaric acid acid, maleic acid and thelike, and a lubricant such as talc and the like. When the protectiveagent is used, the amount to be coated is about 1-about 15% (w/w),preferably about 1-about 10% (w/w), more preferably about 2-about 8%(w/w), relative to the core.

The protective agent can be coated by a typical coating method.Specifically, the protective agent is, for example, spray-coated to thecore by a fluidized bed coating method, a pan coating method, and thelike.

II. Coating of Core with a Film Forming Agent

The core obtained in the aforementioned I is coated with a film formingliquid agent prepared by dissolving by heating or dissolving ordispersing in a solvent the aforementioned water-insoluble material, apH-dependent swellable polymer, and a hydrophilic material to provide asustained release preparation.

For coating a film forming liquid agent to a core, for example, a spraycoating method and the like can be employed.

The composition ratio of the water-insoluble material, swellable polymeror hydrophilic material in the film forming liquid agent is suitabledetermined such that the content of each component of the coating filmbecomes the aforementioned content.

The coating amount of the film forming agent is about 1-about 90% (w/w),preferably about 5-about 50% (w/w), more preferably about 5-35% (w/w),relative to the core (exclusive of the coating amount of protectiveagent).

As the solvent for the film forming liquid agent, water and organicsolvents can be used alone or in a mixture of the both. The mixing ratio(water/organic solvent: weight ratio) of water and the organic a solventin the mixture can vary within the range of 1-100%, which is preferably1-about 30%. The organic solvent is not subject to any particularlimitation as long as it dissolves the water-insoluble material. Forexample, lower alcohols such as methyl alcohol, ethyl alcohol, isopropylalcohol, n-butyl alcohol and the like, lower alkanone such as acetoneand the like, acetonitrile, chloroform, methylene chloride and the likeare used. Of these, lower alcohol is preferable, and ethyl alcohol andisopropyl alcohol are particularly preferable. Water and a mixture ofwater and an organic solvent is preferably used as a solvent of the filmforming agent. Where necessary, the film forming liquid agent maycontain an acid such as tartaric acid, citric acid, succinic acid,fumaric acid acid, maleic acid and the like for the stabilization of thefilm forming liquid agent.

When spray coating is employed, the method follows a conventionalcoating method, which is specifically spray coating of a film formingliquid agent to the core by, for example, a fluidized bed coatingmethod, a pan coating method and the like. Where necessary, talc,titanium oxide, magnesium stearate, calcium stearate, light anhydroussilicic acid and the like may be added as a lubricant, and glycerinefatty acid ester, hydrogenated castor oil, triethyl citrate, cetylalcohol, stearyl alcohol and the like may be added as a plasticizer.

After coating of a film forming agent, an antistatic agent such as talcand the like may be added as necessary.

A rapid release preparation may be a liquid (solution, suspension,emulsion and the like) or a solid (particles, pill, tablet and thelike). While an oral administration agent, and a parenteraladministration agent, such as injection and the like, are used, withpreference given to an agent for oral administration.

A rapid release preparation may generally contain, in addition to thedrug which is an active ingredient, carriers, additives and excipients(hereinafter sometimes simply referred to as an excipient)conventionally used in the field of preparation. The excipient for apreparation is not subject to any particular limitation as long as it isconventionally employed as an excipient for a preparation. For example,the excipient for the oral solid preparation includes lactose, starch,corn starch, crystalline cellulose (Asahi Kasei Corporation, AvicelPH101 and the like), powder sugar, granulated sugar, mannitol, lightanhydrous silicic acid, magnesium carbonate, calcium carbonate,L-cysteine and the like, preferably corn starch and mannitol and thelike. These excipients may be used alone or in combination. The contentof the excipient is, for example, about 4.5-about 99.4 w/w %, preferablyabout 20-about 98.5 w/w %, more preferably about 30-about 97 w/w %,relative to the total amount of the rapid release preparation.

The drug content of the rapid release preparation is appropriatelydetermined from the range of about 0.5-about 95%, preferably about1-about 60%, relative to the total amount of the rapid releasepreparation.

When the rapid release preparation is an oral solid preparation, itgenerally contains a disintegrator in addition to the above-mentionedcomponents. Examples of the disintegrator include calciumcarboxymethylcellulose (manufactured by Gotoku Yakuhin, ECG-505),crosscarmelose sodium (e.g., Asahi Kasei Corporation, Actisol),Crospovidone (e.g., Colicone CL, BASF), low substitutedhydroxypropylcellulose (Shin-Etsu Chemical Co., Ltd.), carboxymethylstarch (Matsutani Chemical Industry Co., Ltd., sodium carboxymethylstarch (manufactured by Kimura Sangyo, Exprotab), partially a starch(PCS, Asahi Kasei Corporation) and the like. For example, one capable ofdisintegrating granules by water absorption, swelling, forming a channelbetween the active ingredient constituting the core and an excipientupon contact with water and the like can be used. These disintegratorscan be used alone or in combination. The amount of the disintegrator isappropriately determined depending on the kind of the combination drugto be used and amount thereof, design of the release preparation and thelike. It is generally about 0.05-about 30 w/w %, preferably about0.5-about 15 w/w %, relative to the total amount of the rapid releasepreparation.

When the rapid release preparation is an oral preparation, the oralsolid preparation may further contain, in addition to theabove-mentioned composition, routine additives used for solidpreparation on demand. Examples of the additive include a binder (e.g.,sucrose, gelatin, gum arabic powder, methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose,carboxymethylcellulose, polyvinylpyrrolidone, Pullulan, dextrin and thelike), a lubricant (e.g., polyethylene glycol, magnesium stearate, talc,light anhydrous silicic acid (e.g., Aerosil (Nippon Aerosil)), asurfactant (e.g., anionic surfactant such as sodium alkylsulfate and thelike, non-ionic surfactant such as polyoxyethylene fatty acid ester andpolyoxyethylenesorbitan fatty acid ester, polyoxyethylene castor oilderivative and the like, and the like), a coloring agent (e.g.,synthetic color, caramel, iron oxide red, titanium oxide, riboflavins),where necessary, a corrigent (e.g., a sweetener, flavor and the like),an absorbent, an antiseptic, a moistening agent, an antistatic agent andthe like. As the stabilizer, an organic acid such as tartaric acid,citric acid, succinic acid, fumaric acid and the like may be added.

Examples of the above-mentioned binder preferably includehydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone andthe like.

The rapid release preparation can be prepared based on the conventionalpreparation method, by mixing each of the aforementioned components, andwhere necessary, further kneading and forming. The above-mentionedmixing can be performed by a conventional method, such as mixing,kneading and the like. Specifically, for example, when a rapid releasepreparation is formed into particles, a vertical granulator, a universalkneader (manufactured by Hata Tekkosho), a fluidized bed granulatorFD-5S (Powrex Corporation) and the like are used for mixing, which isfollowed by granulating by wet extrusion granulation, fluidized bedgranulation and the like, to give the preparation, as in the preparationof the core of the aforementioned sustained release preparation.

The rapid release preparation and the sustained release preparation thusobtained may be used as they are. Alternatively, after suitable separatepreparation along with an excipient for a preparation and the likeaccording to a conventional method, they may be administeredsimultaneously or at optional administration intervals. Alternatively,they may be prepared into a single preparation for oral administration(e.g., granule, subtilized granule, tablet, capsule and the like) asthey are or along with excipient for preparation and the like asappropriate. The both preparations are converted to granules orsubtilized granules and filled in a single capsule and the like to givea preparation for oral administration.

[3] A Sublingual Tablet, Buccal or Oral Cavity Rapid Disintegrator andPreparation Thereof

The sublingual tablet, buccal preparation and oral cavity rapiddisintegrator may be a solid preparation such as tablet and the like oran oral cavity mucous membrane adhesion tablet (film).

As the sublingual tablet, buccal or oral cavity rapid disintegrator, apreparation containing a combination drug and an excipient ispreferable. It may contain auxiliaries such as a lubricant, an isotonicagent, a hydrophilic carrier, a water dispersible polymer, a stabilizerand the like. For easy absorption and enhanced bioavailability,β-cyclodextrin or β-cyclodextrin derivative (e.g.,hydroxypropyl-β-cyclodextrin and the like) and the like may becontained.

Examples of the above-mentioned excipient include lactose, sucrose,D-mannitol, starch, crystalline cellulose, light anhydrous silicic acidand the like. Examples of the lubricant include magnesium stearate,calcium stearate, talc, colloidal silica and the like, particularlymagnesium stearate and colloidal silica are preferable. Examples of theisotonic agent include sodium chloride, glucose, fructose, mannitol,sorbitol, lactose, saccharose, glycerine, urea and the like,particularly mannitol is preferable. Examples of the hydrophilic carrierinclude swellable hydrophilic carriers such as crystalline cellulose,ethylcellulose, crosslinked polyvinylpyrrolidone, light anhydroussilicic acid, silicic acid, dicalcium phosphate, calcium carbonate andthe like, particularly crystalline cellulose (e.g., microcrystallinecellulose and the like) is preferable. Examples of the water dispersiblepolymer include gum (e.g., gum tragacanth, acacia gum, guar gum),alginate (e.g., sodium alginate), cellulose derivative (e.g.,methylcellulose, carboxymethylcellulose, hydroxymethylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose), gelatin, solublestarch, polyacrylic acid (e.g., carbomer), polymethacrylic acid,polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone,polycarbofil, ascorbic palmitate and the like, with preference given tohydroxypropylmethylcellulose, polyacrylic acid, alginate, gelatin,carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol andthe like. Particularly, hydroxypropylmethylcellulose is preferable.Examples of the stabilizer include cysteine, thiosorbitol, tartaricacid, citric acid, sodium carbonate, ascorbic acid, glycine, sodiumsulfite and the like, particularly, citric acid and ascorbic acid arepreferable.

The sublingual tablet, buccal and oral cavity rapid disintegrator can beproduced by mixing a combination drug and an excipient by a method knownper se. Where desired, the above-mentioned auxiliaries such as alubricant, an isotonic agent, a hydrophilic carrier, a water dispersiblepolymer, a stabilizer, a coloring agent, a sweetener, an antiseptic andthe like may be contained. After mixing the above-mentioned componentssimultaneously or with time staggering, the mixture is compressionformed under pressure to give sublingual tablet, buccal or oral cavityrapid disintegrator. To achieve a suitable hardness, a solvent such aswater, alcohol and the like is used to moisten or wet as necessarybefore and after the compession forming. After the forming, the tabletsare dried.

When a mucous membrane adhesion tablet (film) is produced, a combinationdrug and the above-mentioned water dispersible polymer (preferably,hydroxypropylcellulose, hydroxypropylmethylcellulose), an excipient andthe like are dissolved in a solvent such as water and the like, and theobtained solution is cast to give a film. In addition, an additive suchas a plasticizer, a stabilizer, an antioxidant, a preservative, acoloring agent, a buffer, a sweetener and the like may be added. Toimpart suitable elasticity to the film, glycols such as polyethyleneglycol, propylene glycol and the like may be added, and to increaseadhesion of the film to the oral cavity mucous membrane lining,bioadhesive polymer (e.g., polycarbofil, carbopol) may be added. Thecasting includes pouring the solution on a non-adhesive surface,spreading the solution in a uniform thickness (preferably about10-1000μ) with a coating tool such as doctor blade and the like anddrying the solution to give a film. The film thus formed may be dried atroom temperature or under heating and cut into a desired surface area.

Examples of preferable oral cavity rapid disintegrator is a solid rapiddiffusing administration agent having a net structure of a combinationdrug and water soluble or water diffusable carrier which are inert tothe combination drug. The net structure can be obtained by sublimationof a solvent from the solid composition consisting of a solutionobtained by dissolving a combination drug in a suitable solvent.

The oral cavity rapid disintegrator preferably contains, in addition tothe combination drug, a matrix forming agent and a secondary component.

Examples of the matrix forming agent include animal proteins orvegetable proteins such as gelatins, dextrins, soybeans, wheat, psylliumseed protein and the like; rubber substances such as gum arabic, guargum, agar, xanthan and the like; polysaccharides; alginic acids;carboxymethylcelluloses; carragheenans; dextrans; pectins; syntheticpolymers such as polyvinylpyrrolidone and the like; a material derivedfrom a gelatin-gum arabic complex and the like. In addition, saccharidessuch as mannitol, dextrose, lactose, galactose, trehalose and the like;cyclic saccharides such as cyclodextrin and the like; inorganic saltssuch as sodium phosphate, sodium chloride, aluminum silicate and thelike; amino acid having 2 to 12 carbon atoms such as glycine, L-alanine,L-aspartic acid, L-glutamine acid, L-hydroxyproline, L-isoleucine,L-leucine, L-phenylalanine and the like are exemplified.

It is possible to introduce one or more matrix forming agents into asolution or suspension before preparation into a solid. Such matrixforming agent may exist with a surfactant or without a surfactant. Thematrix forming agent can form a matrix, and also can help maintain thediffusion of the inventive Compound or a combination drug in thesolution or suspension.

The composition may contain a secondary component such as apreservative, an antioxidant, a surfactant, a thickener, a coloringagent, a pH adjusting agent, a flavor, a sweetener, a taste maskingreagent and the like. Examples of a suitable coloring agent include red,black and yellow ferric oxides and FD&C dyes of Elis and Eberald, suchas FD&C blue NO. 2, FD&C red No. 40 and the like. A suitable flavorcontains mint, raspberry, licorice, orange, lemon, grapefruit, caramel,vanilla, cherry, grape flavor and a combination of these. Suitable pHadjusting agent includes citric acid, tartaric acid, phosphoric acid,hydrochloric acid and maleic acid. Suitable sweetener includesaspartame, acesulfame K, thaumatin and the like. Suitable taste maskingagent includes sodium bicarbonate, ion exchange resin, cyclodextrininclusion compound, adsorbent substance and microcapsuled apomorphine.

The preparation contains a combination drug generally in a proportion ofabout 0.1-about 50 wt %, preferably about 0.1-about 30 wt %, and iscapable of dissolving 90% or more of a combination drug in water forabout 1 min-about 60 min, preferably about 1 min-about 15 min, morepreferably about 2 min-about 5 min, such as the above-mentionedsublingual tablet, buccal and the like, and an oral cavity rapiddisintegrator that disintegrates within 1-60 sec. preferably 1-30 sec,more preferably 1-10 sec, after being placed in an oral cavity ispreferable.

The content of the above-mentioned excipient in the whole preparation isabout 10-about 99 wt %, preferably about 30-about 90 wt %. The contentof the β-cyclodextrin or β-cyclodextrin derivative relative to the wholepreparation is 0-about 30 wt %. The content of the lubricant relative tothe whole preparation is about 0.01-about 10 wt %, preferably about1-about 5 wt %. The content of the isotonic agent relative to the wholepreparation is about 0.1-about 90 wt %, preferably about 10-about 70 wt%. The content of the hydrophilic carrier relative to the wholepreparation is about 0.1-about 50 wt %, preferably about 10-about 30 wt%. The content of the water dispersible polymer relative to the wholepreparation is about 0.1-about 30 wt %, preferably about 10-about 25 wt%. The content of the stabilizer relative to the whole preparation isabout 0.1-about 10 wt %, preferably about 1-about 5 wt %. Theabove-mentioned preparation may contain additives such as a coloringagent, a sweetener, an antiseptic and the like as necessary.

While the dose of the pharmaceutical composition of the combination drugvaries depending on the kind of the combination drug, the patient's age,body weight and condition, the dosage form, the mode and the period ofthe treatment, the amount of the combination drug may, for example, begenerally about 0.01 to about 1000 mg/kg, preferably about 0.01 to about100 mg/kg, more preferably about 0.1 to about 100 mg/kg, most preferablyabout 0.1 to about 50 mg/kg, and particularly about 1.5 to about 30mg/kg per day in a patient (adult weighing about 60 kg), said daily dosebeing given intravenously all at once or in several portions during aday. It is a matter of course that a lower daily dose may be sufficientor an excessive dose may be required since the dose may vary dependingon various factors as discussed above.

The combination drug may be contained in any amount as long as a sideeffect does not pose a problem. While the daily dose of the combinationdrug may vary depending on the disease state, the age, sex, body weightand difference in sensitivity of the administration object, timing andinterval of administration, characteristics of the pharmaceuticalpreparation, dispensing, kind, the kind of active ingredient and thelike and is not particularly limited, the amount of the drug isgenerally about 0.001-2000 mg, preferably about 0.01-500 mg, morepreferably about 0.1-100 mg, per 1 kg body weight of mammal by oraladministration, which is generally administered all at once or in 2 to 4portions during a day.

When the composition of the present invention and the pharmaceuticalcomposition of a combination drug are concurrently administered, theymay be administered at the same time, or the pharmaceutical compositionof a combination drug may be administered first, and then thecomposition of the present invention may be administered. Alternatively,the composition of the present invention may be administered first, andthen the pharmaceutical composition of a combination drug may beadministered. For time stagger administration, the time differencevaries depending on the active ingredient to be administered, dosageform and administration route. For example, when the pharmaceuticalcomposition of a combination drug is to be administered first, thecomposition of the present invention is administered within 1 min-3days, preferably 10 min-1 day, more preferably 15 min-1 hour, after theadministration of the pharmaceutical composition of a combination drug.When the composition of the present invention is to be administeredfirst, the pharmaceutical composition of a combination drug isadministered within 1 min-1 day, preferably 10 min-6 hours, morepreferably 15 min-1 hour, after the administration of the composition ofthe present invention.

EXAMPLES

The present invention is further described with referring to ReferenceExamples, Examples and Experiments, which are not intended to restrictthe invention.

A ¹H NMR spectrum was determined by a VARIAN GEMINI 200 (200 MHz)spectrometer using tetramethyl silane as an internal standard andrepresented as the entire 6 values in ppm. The number in a bracket whena solvent mixture was employed is the volume ratio of each mixture. A %is a % by weight unless otherwise specified. The ratio of the solventsin a chromatography on silica gel is the volume ratio of the solvents tobe admixed.

A more polar diastereomer means a diastereomer having a smaller Rf valuewhen determined by a normal phase thin layer chromatography under a samecondition (for example using ethyl acetate/hexane as an eluent), which aless polar diastereomer means a diastereomer having a larger Rf value insuch determination.

The meanings of the abbreviations as used in the Examples are asfollows:

s: singlet d: doublet: t: triplet q: quartet

DD: double doublet tt: triple triplet m: multiplet br: broad J: couplingconstant

The Reference Example A to be mentioned below can be produced accordingto Reference Example of WO99/46424 and Reference Example B can beproduced according to Example of WO99/46424.

Reference Example A

-   Reference Example A1 ethyl 2-sulfo-1-cyclohexene-1-carboxylate-   Reference Example A2 ethyl    2-chlorosulfonyl-1-cyclohexene-1-carboxylate-   Reference Example A3 ethyl    2-chlorosulfonyl-1-cyclopentene-1-carboxylate-   Reference Example A4 ethyl    2-chlorosulfonyl-1-cycloheptene-1-carboxylate-   Reference Example A5    6-[N-(4-chloro-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylic    acid sodium salt-   Reference Example A6 1-(3-fluoro-4-nitrophenyl)-1H-1,2,4-triazole-   Reference Example A7 1-(4-amino-3-fluorophenyl)-1H-1,2,4-triazole-   Reference Example A8 methyl    4-benzyloxycarbonylamino-3-chlorobenzoate-   Reference Example A9 4-benzyloxycarbonylamino-3-chlorobenzoic acid-   Reference Example A10 tert-butyl    N-(4-benzyloxycarbonylamino-3-chlorobenzoyl)glycinate-   Reference Example A11 tert-butyl    N-(4-amino-3-chlorobenzoyl)glycinate-   Reference Example A12    6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylic acid-   Reference Example A13 ethyl    2-mercapto-5-phenyl-1-cyclohexene-1-carboxylate-   Reference Example A14    2-chlorosulfonyl-5-phenyl-1-cyclohexene-1-carboxylate-   Reference Example A15 ethyl    5-tert-butyl-2-mercapto-1-cyclohexene-1-carboxylate-   Reference Example A16 ethyl    5-tert-butyl-2-chlorosulfonyl-1-cyclohexene-1-carboxylate-   Reference Example A17 ethyl    5,5-dimethyl-2-mercapto-1-cyclohexene-1-carboxylate-   Reference Example A18 ethyl    2-chlorosulfonyl-5,5-dimethyl-1-cyclohexene-1-carboxylate

Reference Example B

-   Reference Example B1 ethyl    6-[N-(4-chloro-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 1)-   Reference Example B2 ethyl    6-[N-(4-chloro-2-fluorophenyl)-N-methylsulfamoyl]-1-cyclohexene-1-carboxylate    (compound 2)-   Reference Example B3 ethyl    6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 3)-   Reference Example B4 ethyl    6-[N-(2,6-diisopropylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 4)-   Reference Example B5 ethyl    6-[N-(4-nitrophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (compound    5)-   Reference Example B6 ethyl    6-(N-phenylsulfamoyl)-1-cyclohexene-1-carboxylate (compound 6) ethyl    2-(N-phenylsulfamoyl)-1-cyclohexene-1-carboxylate (compound 7)-   Reference Example B7 ethyl    2-[N-(4-chloro-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 9)-   Reference Example B8    2-(4-methoxyphenyl)-4,5,6,7tetrahydro-1,2-benzisothiazol-3(2H)-one    1,1-dioxide (compound 67)-   ethyl 2-[N-(4-methoxyphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 8)-   Reference Example B9 ethyl    6-[N-(2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 10)-   Reference Example B10 ethyl    6-[N-(3-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 11)-   Reference Example B11    2-(4-fluorophenyl)-4,5,6,7-tetrahydro-1,2-benzisothiazol-3(2H)-one    1,1-dioxide (compound 68)-   ethyl 6-[N-(4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 12)-   ethyl 2-[N-(4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 18)-   Reference Example B12 ethyl    6-[N-(2,6-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 13)-   Reference Example B13 ethyl    6-[N-(2,3-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 14)-   Reference Example B14 ethyl    6-[N-(2,5-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 15)-   Reference Example B15 ethyl    6-[N-(3,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 16)-   Reference Example B16 ethyl    6-[N-(3,5-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 17)-   Reference Example B17 1-ethyl    6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 19)-   d-ethyl    6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 20)-   Reference Example B18 ethyl    6-[N-(2-ethoxycarbonylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 21)-   Reference Example B19 methyl    6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 22)-   Reference Example B20 propyl    6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 23)-   Reference Example B21 methyl    6-[N-(4-chloro-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 24)-   Reference Example B22 isopropyl    6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 25)-   Reference Example B23 ethyl    6-[N-(2-methoxycarbonylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 26)-   Reference Example B24 ethyl    6-[N-(2-fluoro-4-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 27)-   Reference Example B25 ethyl    6-[N-(2-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 28)-   Reference Example B26 ethyl    6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 29)-   Reference Example B27 ethyl    6-[N-(4-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 30)-   Reference Example B28 ethyl    6-[N-(2,3,4-trifluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 31)-   Reference Example B29 isobutyl    6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 32)-   Reference Example B30 butyl    6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 33)-   Reference Example B31 ethyl    6-[N-(4-bromo-2-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 34)-   Reference Example B32 ethyl    6-[N-(2,4-dichlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 35)-   Reference Example B33 ethyl    6-[N-(2-acetoxyphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 36)-   Reference Example B34 ethyl    6-[N-(3-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 37)-   Reference Example B35 ethyl    6-[N-(2,3-dichlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 38)-   Reference Example B36 ethyl    6-[N-(2-ethylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (compound    39)-   Reference Example B37 ethyl    6-[N-[4-(2H-1,2,3-triazol-2-yl)phenyl]sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 40)-   Reference Example B38 ethyl    6-[N-(2,5-dichlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 41)-   Reference Example B39 ethyl    6-[N-(2-trifluoromethoxyphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 42)-   Reference Example B40 ethyl    6-[N-(2,4,5-trifluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 43)-   Reference Example B41 ethyl    6-[N-[4-(2H-tetrazol-2-yl)phenyl]sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 44)-   Reference Example B42 ethyl    6-[N-(2-chloro-4-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 45)-   Reference Example B43 ethyl    6-[N-(4-fluoro-2-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 46)-   Reference Example B44 ethyl    6-[N-(2,6-dichlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 47)-   Reference Example B45 ethyl    6-[N-[4-(1H-tetrazol-1-yl)phenyl]sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 48)-   Reference Example B46 ethyl    6-[N-(4-(1H-1,2,3-triazol-1-yl)phenyl]sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 49)-   Reference Example B47 ethyl    6-[N-(2-trifluoromethylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 50)-   Reference Example B48 ethyl    6-[N-(4-methoxycarbonylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 51)-   Reference Example B49 benzyl    6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 52)-   Reference Example B50 ethyl    6-[N-[4-[2,3-bis(tert-butoxycarbonyl)guanidinomethyl]phenyl]sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 53)-   Reference Example B51 ethyl    6-[N-(2-chloro-4-methoxycarbonylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 54)-   Reference Example B52 ethyl    6-[N-(2-chloro-4-cyanophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 55)-   Reference Example B53 2-hydroxyethyl    6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 56)-   Reference Example B54 ethyl    6-[N-[2-fluoro-4-(1H-1,2,4-triazol-1-yl)phenyl]sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 57)-   Reference Example B55 ethyl    2-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclopentene-1-carboxylate    (compound 66)-   ethyl    5-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclopentene-1-carboxylate    (compound 58)-   Reference Example B56 tert-butyl    [6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexen-1-yl]carbonyloxyacetate    (compound 59)-   Reference Example B57    [6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexen-1-yl]carbonyloxyacetic    acid (compound 60)-   Reference Example B58 ethyl    7-[N-(2,4-difluorophenyl)sulfamoyl]-1-cycloheptene-1-carboxylate    (compound 61)-   Reference Example B59 ethyl    6-[N-[2-chloro-4-(N-tert-butoxycarbonylmethylcarbamoyl)phenyl]sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 62)-   Reference Example B60 ethyl    6-[N-[2-chloro-4-(N-ethoxycarbonylmethylcarbamoyl)phenyl]sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 63)-   Reference Example B61 ethyl    5-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclopentene-1-carboxylate    (compound 64).-   Reference Example B62    2-[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]-4,5,6,7-tetrahydro-1,2-benzisothiazol-3(2H)-one    1,1-dioxide (compound 69)-   Reference Example B63 ethyl    7-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-dycloheptene-1-carboxylate    (compound 65)-   Reference Example B64    2-(2,4-difluorophenyl)-5,6,7,7a-tetrahydro-1,2-benzisothiazol-3(2H)-one    1,1-dioxide (compound 70)-   Reference Example B65 ethyl    6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 29)-   Reference Example B66 1-ethyl    6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 71)-   d-ethyl    6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 72)-   Reference Example B67 ethyl    6-[N-(2-bromo-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 73)-   Reference Example B68 ethyl    6-[N-(4-bromo-2-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 74)-   Reference Example B69 high polarity diastereomer (compound 75) and    low polarity diastereomer (compound 76) of ethyl    6-[N-(2,4-difluorophenyl)sulfamoyl]-3-phenyl-1-cyclohexene-1-carboxylate-   Reference Example B70 high polarity diastereomer (compound 77) and    low polarity diastereomer (compound 78) of ethyl    6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-phenyl-1-cyclohexene-1-carboxylate-   Reference Example B71 high polarity diastereomer (compound 79) and    low polarity diastereomer (compound 80) of ethyl    6-[N-(2,4-difluorophenyl)sulfamoyl]-3-tert-butyl-1-cyclohexene-1-carboxylate-   Reference Example B72 high polarity diastereomer (compound 81) and    low polarity diastereomer (compound 82) of ethyl    6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3-tert-butyl-1-cyclohexene-1-carboxylate-   Reference Example B73 ethyl    6-[N-(2,4-difluorophenyl)sulfamoyl]-3,3-dimethyl-1-cyclohexene-1-carboxylate    (compound 83)-   Reference Example B74 ethyl    6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethyl-1-cyclohexene-1-carboxylate    (compound 84)-   Reference Example B75 ethyl    3-bromo-6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate    (compound 85)

Specific examples are shown in Tables 1-12.

TABLE 1

Compound No. R¹ R² Ar n 1 C₂H₅ H

2 2 C₂H₅ CH₃

2 3 C₂H₅ H

2 4 C₂H₅ H

2 5 C₂H₅ H

2 6 C₂H₅ H

2 10 C₂H₅ H

2

TABLE 2 11 C₂H₅ H

2 12 C₂H₅ H

2 13 C₂H₅ H

2 14 C₂H₅ H

2 15 C₂H₅ H

2 16 C₂H₅ H

2 17 C₂H₅ H

2 19 (l-compound) C₂H₅ H

2 20 (d-compound) C₂H₅ H

2

TABLE 3 21 C₂H₅ H

2 22 CH₃ H

2 23 (CH₂)₂CH₃ H

2 24 CH₃ H

2 25 CH(CH₃)₂ H

2 26 C₂H₅ H

2 27 C₂H₅ H

2 28 C₂H₅ H

2 29 C₂H₅ H

2 30 C₂H₅ H

2

TABLE 4 31 C₂H₅ H

2 32 CH₂CH(CH₃)₂ H

2 33 (CH₂)₃CH₃ H

2 34 C₂H₅ H

2 35 C₂H₅ H

2 36 C₂H₅ H

2 37 C₂H₅ H

2 38 C₂H₅ H

2 39 C₂H₅ H

2 40 C₂H₅ H

2

TABLE 5 41 C₂H₅ H

2 42 C₂H₅ H

2 43 C₂H₅ H

2 44 C₂H₅ H

2 45 C₂H₅ H

2 46 C₂H₅ H

2 47 C₂H₅ H

2 48 C₂H₅ H

2 49 C₂H₅ H

2 50 C₂H₅ H

2

TABLE 6 51 C₂H₅ H

2 52

H

2 53 C₂H₅ H

2 54 C₂H₅ H

2 55 C₂H₅ H

2 56 (CH₂)₂OH H

2 57 C₂H₅ H

2 58 C₂H₅ H

1 59 CH₂COOC(CH₃)₃ H

2 60 CH₂COOH H

2

TABLE 7 61 C₂H₅ H

3 62 C₂H₅ H

2 63 C₂H₅ H

2 64 C₂H₅ H

1 65 C₂H₅ H

3 71 (l- compound) C₂H₅ H

2 72 (d- compound) C₂H₅ H

2 73 C₂H₅ H

2 74 C₂H₅ H

2

TABLE 8

Compound No. R¹ Ar n 7 C₂H₅

2 8 C₂H₅

2 9 C₂H₅

2 18 C₂H₅

2 66 C₂H₅

1

TABLE 9

Compound No.

Ar 67

68

69

70

TABLE 10

Compound No. R¹ R² R* Ar 75 (high polarity diastereomer) C₂H₅ H

76 (low polarity diastereomer) C₂H₅ H

77 (high polarity diastereomer) C₂H₅ H

78 (low polarity diastereomer) C₂H₅ H

79 (high polarity diastereomer) C₂H₅ H C(CH₃)₃

80 (low polarity diastereomer) C₂H₅ H C(CH₃)₃

81 (high polarity diastereomer) C₂H₅ H C(CH₃)₃

TABLE 11 82 (low polarity diastereomer) C₂H₅ H C(CH₃)₃

85 C₂H₅ H Br

TABLE 12

Compound No. Ar 83

84

Example 1

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidylglycerol 1 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddimyristoylphosphatidylglycerol (2 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 2

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidylglycerol 2 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddimyristoylphosphatidylglycerol (4 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 3

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidylglycerol 5 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddimyristoylphosphatidylglycerol (10 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 4

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidylglycerol 10 mg 6) distilled water total amount100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddimyristoylphosphatidylglycerol (20 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 5

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidylglycerol 20 mg 6) distilled water total amount100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddimyristoylphosphatidylglycerol (40 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 6

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidylglycerol 1 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidylglycerol (2 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 7

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidylglycerol 2 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidylglycerol (4 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 8

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidylglycerol 5 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidylglycerol (10 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 9

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidylglycerol 10 mg 6) distilled water total amount100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidylglycerol (20 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 10

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidylglycerol 20 mg 6) distilled water total amount100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidylglycerol (40 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer.(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 11

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)distearoylphosphatidylglycerol 1 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddistearoylphosphatidylglycerol (2 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 12

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)distearoylphosphatidylglycerol 2 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddistearoylphosphatidylglycerol (4 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 13

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)distearoylphosphatidylglycerol 5 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddistearoylphosphatidylglycerol (10 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 14

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)distearoylphosphatidylglycerol 10 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddistearoylphosphatidylglycerol (20 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 15

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)distearoylphosphatidylglycerol 20 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddistearoylphosphatidylglycerol (40 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 16

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidylglycerol 1 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidylglycerol (2 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 17

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidylglycerol 2 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidylglycerol (4 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 18

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidylglycerol 5 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidylglycerol (10 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 19

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidylglycerol 10 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidylglycerol (20 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 20

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidylglycerol 20 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidylglycerol (40 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 21

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)oleoylpalmitoylphosphatidylglycerol 1 mg 6) distilled water total amount100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) andoleoylpalmitoylphosphatidylglycerol (2 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 22

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)oleoylpalmitoylphosphatidylglycerol 2 mg 6) distilled water total amount100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) andoleoylpalmitoylphosphatidylglycerol (4 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 23

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)oleoylpalmitoylphosphatidylglycerol 5 mg 6) distilled water total amount100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) andoleoylpalmitoylphosphatidylglycerol (10 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 24

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)oleoylpalmitoylphosphatidylglycerol 10 mg 6) distilled water totalamount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) andoleoylpalmitoylphosphatidylglycerol (20 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 25

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)oleoylpalmitoylphosphatidylglycerol 20 mg 6) distilled water totalamount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) andoleoylpalmitoylphosphatidylglycerol (40 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 26

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioctanoylphosphatidic acid 1 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioctanoylphosphatidic acid (2 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 27

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioctanoylphosphatidic acid 2 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioctanoylphosphatidic acid (4 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 28

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioctanoylphosphatidic acid 5 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioctanoylphosphatidic acid (10 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 29

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioctanoylphosphatidic acid 10 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioctanoylphosphatidic acid (20 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 30

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioctanoylphosphatidic acid 20 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioctanoylphosphatidic acid (40 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 31

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)didecanoylphosphatidic acid 1 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddidecanoylphosphatidic acid (2 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 32

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)didecanoylphosphatidic acid 2 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddidecanoylphosphatidic acid (4 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 33

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)didecanoylphosphatidic acid 5 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddidecanoylphosphatidic acid (10 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 34

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)didecanoylphosphatidic acid 10 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddidecanoylphosphatidic acid (20 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 35

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)didecanoylphosphatidic acid 20 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddidecanoylphosphatidic acid (40 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 36

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dilauroylphosphatidic acid 1 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddilauroylphosphatidic acid (2 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 37

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dilauroylphosphatidic acid 2 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddilauroylphosphatidic acid (4 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 38

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dilauroylphosphatidic acid 5 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddilauroylphosphatidic acid (10 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 39

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dilauroylphosphatidic acid 10 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddilauroylphosphatidic acid (20 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 40

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dilauroylphosphatidic acid 20 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddilauroylphosphatidic acid (40 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 41

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidic acid 1 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddimyristoylphosphatidic acid (2 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 42

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidic acid 2 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddimyristoylphosphatidic acid (4 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 43

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidic acid 5 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddimyristoylphosphatidic acid (10 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 44

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidic acid 10 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddimyristoylphosphatidic acid (20 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 45

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidic acid 20 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddimyristoylphosphatidic acid (40 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 46

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidic acid 1 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidic acid (2 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 47

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidic acid 2 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidic acid (4 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 48

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidic acid 5 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidic acid (10 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 49

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidic acid 10 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidic acid (20 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 50

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidic acid 20 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidic acid (40 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 51

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)distearoylphosphatidic acid 1 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddistearoylphosphatidic acid (2 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 52

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)distearoylphosphatidic acid 2 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddistearoylphosphatidic acid (4 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 53

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)distearoylphosphatidic acid 5 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddistearoylphosphatidic acid (10 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 54

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)distearoylphosphatidic acid 10 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddistearoylphosphatidic acid (20 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 55

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)distearoylphosphatidic acid 20 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddistearoylphosphatidic acid (40 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 56

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidic acid 1 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidic acid (2 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 57

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidic acid 2 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidic acid (4 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 58

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidic acid 5 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidic acid (10 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 59

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidic acid 10 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (46 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidic acid (20 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 60

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidic acid 20 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidic acid (40 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 61

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidylserine 1 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidylserine (2 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 62

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidylserine 2 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidylserine (4 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 63

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidylserine 5 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidylserine (10 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 64

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidylserine 10 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidylserine (20 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 65

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidylserine 20 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidylserine (40 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 66

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidylserine 1 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidylserine (2 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 67

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidylserine 2 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidylserine (4 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 68

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidylserine 5 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidylserine (10 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 69

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidylserine 10 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidylserine (20 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 70

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidylserine 20 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), 15′ purified egg yolk lecithin (2.4 g)and dioleoylphosphatidylserine (40 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water.

Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 71

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidylglycerol 200 mg 6) distilled water total amount100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddimyristoylphosphatidylglycerol (400 mg) were dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume was adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion wasfinely emulsified. The obtained emulsion composition was passed througha membrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules were heat-sealed. The ampoules were sterilized in an autoclaveat 121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 72

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidylglycerol 200 mg 6) distilled water total amount100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidylglycerol (400 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 73

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)distearoylphosphatidylglycerol 200 mg 6) distilled water total amount100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddistearoylphosphatidylglycerol (400 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 74

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidylglycerol 200 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidylglycerol (400 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 75

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)oleoylpalmitoylphosphatidylglycerol 200 mg 6) distilled water totalamount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) andoleoylpalmitoylphosphatidylglycerol (400 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 76

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioctanoylphosphatidic acid 200 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioctanoylphosphatidic acid (400 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 77

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)didecanoylphosphatidic acid 200 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddidecanoylphosphatidic acid (400 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 78

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dilauroylphosphatidic acid 200 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddilauroylphosphatidic acid (400 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 79

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidic acid 200 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddimyristoylphosphatidic acid (400 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C.; These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 80

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidic acid 200 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidic acid (400 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 81

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)distearoylphosphatidic acid 200 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddistearoylphosphatidic acid (400 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 82

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidic acid 200 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidic acid (400 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 83

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidylserine 200 mg 6) distilled water total amount 100ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddipalmitoylphosphatidylserine (400 mg) are dissolved/dispersed indistilled water (125 ml) at 60° C. These are mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1min. The volume is adjusted to 200 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure for 40 minutes, the crude emulsion isfinely emulsified. The obtained emulsion composition is passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 2 ml ampoules by 2 ml. After nitrogen displacement, theampoules are heat-sealed. The ampoules are sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 84

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dioleoylphosphatidylserine 200 mg 6) distilled water total amount 100 ml

Compound 72 (2000 mg) of Reference Example B66 is dissolved in soybeanoil (40 g). Glycerine (4.5 g), purified egg yolk lecithin (2.4 g) anddioleoylphosphatidylserine (400 mg) are dissolved/dispersed in distilledwater (125 ml) at 60° C. These are mixed and roughly emulsified in ahomogenizer Polytron (ULTRA TURRAX) at 16,000/min for 1 min. The volumeis adjusted to 200 ml in a measuring cylinder with distilled water.Using a high pressure homogenizer microfluidizer (Mizuho) at 15000 psipressure for 40 minutes, the crude emulsion is finely emulsified. Theobtained emulsion composition is passed through a membrane filter(Millipore Sterivex-HV) having a pore size of 0.45 μm, and filled in 2ml ampoules by 2 ml. After nitrogen displacement, the ampoules areheat-sealed. The ampoules are sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 85

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidylglycerol 50 mg 6) distilled water total amount100 ml

Compound 72 (9452 mg) of Reference Example B66 was dissolved in soybeanoil (180 g). Glycerine (20.24 g), purified egg yolk lecithin (10.812 g)and dimyristoylphosphatidylglycerol (452 mg) were dissolved/dispersed indistilled water (560 ml) at 60° C. These were mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 3min. The volume was adjusted to 900 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 8000 psi pressure by 6 pass, the crude emulsion was finelyemulsified. The obtained emulsion composition was passed through amembrane filter (Acrodisc Gelman) having a pore size of 5 μm, and filledin 20 ml vials by 20 ml. After nitrogen displacement, the vials weretightly sealed. The vials were sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 86

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidylglycerol 100 mg 6) distilled water total amount100 ml

Compound 72 (9451 mg) of Reference Example B66 was dissolved in soybeanoil (180 g). Glycerine (20.25 g), purified egg yolk lecithin (10.813 g)and dimyristoylphosphatidylglycerol (905 mg) were dissolved/dispersed indistilled water (560 ml) at 60° C. These were mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 3min. The volume was adjusted to 900 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 8000 psi pressure by 6 pass, the crude emulsion was finelyemulsified. The obtained emulsion composition was passed through amembrane filter (Acrodisc Gelman) having a pore size of 5 μm, and filledin 20 ml vials by 20 ml. After nitrogen displacement, the vials weretightly sealed. The vials were sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 87

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidylglycerol 200 mg 6) distilled water total amount100 ml

Compound 72 (3155 mg) of Reference Example B66 was dissolved in soybeanoil (60 g). Glycerine (6.76 g), purified egg yolk lecithin (3.645 g) anddimyristoylphosphatidylglycerol (610 mg) were dissolved/dispersed indistilled water (188 ml) at 60° C. These were mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 3min. The volume was adjusted to 300 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 15000 psi pressure by 25 pass, the crude emulsion was finelyemulsified. The obtained emulsion composition was passed through amembrane filter (Millipore Sterivex-HV) having a pore size of 0.45 μm,and filled in 30 ml vials by 30 ml. After nitrogen displacement, thevials were tightly sealed. The vials were sterilized in an autoclave at121° C. for 15 min to give an emulsion composition having theabove-mentioned formulation.

Example 88

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidylglycerol 500 mg 6) distilled water total amount100 ml

Compound 72 (9452 mg) of Reference Example B66 was dissolved in soybeanoil (180 g). Glycerine (20.25 g), purified egg yolk lecithin (10.813 g)and dimyristoylphosphatidylglycerol (4506 mg) were dissolved/dispersedin distilled water (560 ml) at 60° C. These were mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 3min. The volume was adjusted to 900 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 8000 psi pressure by 6 pass, the crude emulsion was finelyemulsified. The obtained emulsion composition was passed through amembrane filter (Acrodisc Gelman) having a pore size of 5 μm, and filledin 20 ml vials by 20 ml. After nitrogen displacement, the vials weretightly sealed. The vials were sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 89

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidylglycerol 500 mg 6) distilled water total amount100 ml

Compound 72 (9452 mg) of Reference Example B66 was dissolved in soybeanoil (180 g). Glycerine (20.26 g), purified egg yolk lecithin (8.119 g)and dimyristoylphosphatidylglycerol (4512 mg) were dissolved/dispersedin distilled water (560 ml) at 60° C. These were mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 3min. The volume was adjusted to 900 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 8000 psi pressure by 6 pass, the crude emulsion was finelyemulsified. The obtained emulsion composition was passed through amembrane filter (Acrodisc Gelman) having a pore size of 5 μm, and filledin 20 ml vials by 20 ml. After nitrogen displacement, the vials weretightly sealed. The vials were sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 90

1) compound 72 of Reference Example B66 500 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidylglycerol 200 mg 6) distilled water total amount100 ml

Compound 72 (4725 mg) of Reference Example B66 was dissolved in soybeanoil (180 g). Glycerine (20.26 g), purified egg yolk lecithin (10.811 g)and dimyristoylphosphatidylglycerol (1811 mg) were dissolved/dispersedin distilled water (560 ml) at 60° C. These were mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 3min. The volume was adjusted to 900 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer microfluidizer(Mizuho) at 8000 psi pressure by 6 pass, the crude emulsion was finelyemulsified. The obtained emulsion composition was passed through amembrane filter (Acrodisc Gelman) having a pore size of 5 μm, and filledin 20 ml vials by 20 ml. After nitrogen displacement, the vials weretightly sealed. The vials were sterilized in an autoclave at 121° C. for15 min to give an emulsion composition having the above-mentionedformulation.

Example 91

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dimyristoylphosphatidylglycerol 200 mg 6) distilled water total amount100 ml

Compound 72 (421 mg) of Reference Example B66 was dissolved in soybeanoil (8.03 g). Glycerine (0.91 g), purified egg yolk lecithin (0.48 g)and dimyristoylphosphatidylglycerol (80.1 mg) were dissolved/dispersedin distilled water (30 ml) at 60° C. These were mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 3min. The volume was adjusted to 40 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer MicronLab40 (APVGaulin) at 800 bar pressure by 12 pass, the crude emulsion was finelyemulsified. The obtained emulsion composition was passed through amembrane filter (Millipore Millex-SV) having a pore size of 5 μm, andfilled in 20 ml vials by 15 ml. After nitrogen displacement, the vialswere tightly sealed. The vials were sterilized in an autoclave at 121°C. for 15 min to give an emulsion composition having the above-mentionedformulation.

Example 92

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)dipalmitoylphosphatidylglycerol 200 mg 6) distilled water total amount100 ml

Compound 72 (421 mg) of Reference Example B66 was dissolved in soybeanoil (8.05 g). Glycerine (0.90 g), purified egg yolk lecithin (0.48 g)and dipalmitoylphosphatidylglycerol (81.2 mg) were dissolved/dispersedin distilled water (30 ml) at 60° C. These were mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 3min. The volume was adjusted to 40 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer MicronLab40 (APVGaulin) at 800 bar pressure by 12 pass, the crude emulsion was finelyemulsified. The obtained emulsion composition was passed through amembrane filter (Millipore Millex-SV) having a pore size of 5 μm, andfilled in 20 ml vials by 15 ml. After nitrogen displacement, the vialswere tightly sealed. The vials were sterilized in an autoclave at 121°C. for 15 min to give an emulsion composition having the above-mentionedformulation.

Example 93

1) compound 72 of Reference Example B66 1000 mg 2) soybean oil 20 g 3)purified egg yolk lecithin 1.2 g 4) glycerine 2.25 g 5)distearoylphosphatidylglycerol 200 mg 6) distilled water total amount100 ml

Compound 72 (420 mg) of Reference Example B66 was dissolved in soybeanoil (8.01 g). Glycerine (0.90 g), purified egg yolk lecithin (0.49 g)and distearoylphosphatidylglycerol (79.9 mg) were dissolved/dispersed indistilled water (30 ml) at 60° C. These were mixed and roughlyemulsified in a homogenizer Polytron (ULTRA TURRAX) at 16,000/min for 3min. The volume was adjusted to 40 ml in a measuring cylinder withdistilled water. Using a high pressure homogenizer MicronLab40 (APVGaulin) at 800 bar pressure by 12 pass, the crude emulsion was finelyemulsified. The obtained emulsion composition was passed through amembrane filter (Millipore Millex-SV) having a pore size of 5 μm, andfilled in 20 ml vials by 15 ml. After nitrogen displacement, the vialswere tightly sealed. The vials were sterilized in an autoclave at 121°C. for 15 min to give an emulsion composition having the above-mentionedformulation.

Experiment 1 NO Production-Inhibiting Effect

Mouse macrophage cell line RAW264.7 was used as an iNOS-inducible celland a test compound was examined for its % inhibition of NO production.The test compound was dissolved at 10 mM in N,N-dimethylformamide anddiluted with an RPMI-1640 medium at the concentration of 0.1 mM. Theconcentration was further adjusted using the medium so that a finalconcentration ranging from 10 μM to 10 nM could be obtained by a 10-foldserial dilution and the test compound was added to a culture medium. Onthe day before the experiment, the cell was adjusted at 5×10⁵/ml in anRPMI-1640 medium supplemented with 10% inactivated fetal calf serum andinoculated to a 96-well microplate at 1×10⁵ cells/0.2 ml per well. Afterincubating at 37° C. under an atmosphere of 5% CO₂/95% air overnight,the test compound adjusted as described above was added and then LPS andinterferon gamma were added at the final concentrations of 5 ng/ml and 1U/ml, respectively. After further incubating overnight, culturesupernatants were examined for the concentration of nitrite ion (stablemetabolite of NO) which was used as an index for the NO production. Thenitrite ion concentration was determined by adding 25 μl of 20 μg/ml of2,3-diaminonaphthalene (DAN) to 50 μl of the culture supernatant,followed by incubating at room temperature for 10 minutes, followed byadding 25 μl of 0.5 N NaOH, followed by determining a fluorescence at450 nm (excitation wavelength: 365 nm). The results are shown in Tables13-15. An IC₅₀ represents the concentration of the test compound whichinhibits 50% of the NO production.

TABLE 13 Compound No. IC₅₀ (μM) 1 0.12-0.32 2 1.1 3 0.013-0.039 4 2.6 53.7 6 0.59 7 4.0 8 4.8 9 4.1 10 0.058 11 0.31 12 0.18 13 0.46 14 0.59 150.28 16 0.18 17 2.6 18 4.4 19 2.0 20 0.005 21 2.4 22 0.18 23 0.027 240.78 25 0.32 26 3.3

TABLE 14 27 0.25 28 0.029 29 0.0093 30 0.54 31 0.23 32 0.23 33 0.26 340.35 35 0.082 36 1.5 37 0.13 38 0.041 39 0.32 40 2.5 41 0.24 42 1.1 430.073 44 3.7 45 0.027 46 0.054 47 0.048 48 3.8 49 5.6 50 2.0 51 4.0 524.3 53 2.4 54 2.3

TABLE 15 55 3.3 56 1.0 57 4.6 58 0.39 59 0.54 60 7.9 61 2.8 62 3.8 638.4 64 0.25 65 0.32 66 8.1 67 6.0 68 5.1 69 6.8 70 0.35

In Tables 13-15, Compounds 1 and 3 were tested 7 and 9 times,respectively, and the minimum and the maximum of the IC₅₀ wereindicated.

Any of the test compounds exhibited a potent inhibitory effect on the NOproduction by RAW264.7 cell, revealing that an inventive derivative hadan excellent NO production-inhibiting effect.

Experiment 2 Cytokine Production-Inhibiting Effect

Using mouse macrophage cell line RAW264.7, a test compound was examinedfor its % inhibition of a cytokine production. The test compound wasdissolved at 10 mM in N,N-dimethylformamide and diluted with anRPMI-1640 medium at the concentration of 0.1 mM. The concentration wasfurther adjusted using the medium so that a final concentration rangingfrom 10 μM to 10 nM could be obtained by a 10-fold serial dilution andthe test compound was added to a culture medium. On the day before theexperiment, the cell was adjusted at 5×10⁵/ml in an RPMI-1640 mediumsupplemented with 10% inactivated fetal calf serum and inoculated to a96-well microplate at 1×10⁵ cells/0.2 ml per well. After incubating at37° C. under an atmosphere of 5% CO₂/95% air overnight, the testcompound adjusted as described above was added and then LPS andinterferon-gamma were added at the final concentrations of 5 ng/ml and 1U/ml, respectively. After further incubating overnight, culturesupernatants were examined for the concentrations of TNF-α and IL-6.IL-1α was determined using 1.0 μg/ml of LPS in the absence of interferongamma under otherwise similar conditions. Each cytokine was determinedusing an assay kit manufactured by Amersham. The results are shown inTable 16. An IC₅₀ represents the concentration of the test compoundwhich inhibits 50% of the cytokine production.

TABLE 16 IC₅₀ (μM) Compound No. TNF-α IL-1α IL-6 1 0.20 0.39 0.061 0.530.014

In Table 16, TNF-α and IL-6 were tested twice and each IC₅₀ wasindicated.

Experiment 3 Effect on Increase in Blood Nitric Oxide level

When NO is produced in vivo as a result of a defense mechanism againstinfection or immune abnormality, it is readily metabolized to nitrousacid or nitric acid, resulting in an increase in blood nitric oxideconcentration (NOx). Accordingly, an experimental animal was used toexamine the effect of test compounds on the increase in the blood NOxlevel.

Female BALB/c mice (6 weeks old) were purchased and acclimatized for 1week and assigned to the groups in each of which 6 to 8 animals wereincluded. In a treatment group, 30 mg/kg of a test compound suspended ina 0.5% aqueous solution of methyl cellulose was given orally. In acontrol group, the vehicle was given similarly. After 1 hour, LPS (10mg/kg) was given intraperitoneally to each animal in the treatment andcontrol groups, and the blood was taken 6 hours after the LPSadministration and examined for the serum concentration of nitriteion+nitrate ion. The nitrate ion was converted into the nitrite ionusing a nitrate reductase, and the measured values, which was obtainedby the fluorescent method using DAN described above, were represented asthe total nitrite ion concentration. A % inhibition in a treatment groupwhen compared with the control group is shown in Table 17.

TABLE 17 Compound No. NO_(x) inhibition (%) in blood 1 76 3 90Experiment 4 Effect on Increase in Blood Cytokine Level

As a result of a defense mechanism against an infection or an immuneabnormality, various in vivo cytokines are produced. Accordingly, anexperimental animal model was used to examine the effect of a testcompound on the increase in the blood cytokine level.

Female BALB/c mice (6 weeks old) were purchased and acclimatized for 1week and assigned to the groups in each of which 6 to 8 animals wereincluded. In a treatment group, 30 mg/kg of a test compound suspended ina 0.5% aqueous solution of methyl cellulose was given orally. In acontrol group, the vehicle was given similarly. After 1 hour, LPS (10mg/kg) was given intraperitoneally to each animal in the treatment andcontrol groups, and the blood was taken 1 hour after the LPSadministration and examined for the serum concentrations of TNF-α.IL-1α, IL-1β and IL-6 concentrations were determined using the serumfrom the blood taken 6 hours after the LPS administration. A %inhibition in a treatment group when compared with the control group isshown in Table 18. Each cytokine was determined using an assay kitmanufactured by Amersham.

TABLE 18 cytokine inhibition (%) in blood Compound No. TNF-α IL-1α IL-1βIL-6 1 98 97 73 89

As evident from Table 18, Compound (I) has an excellent inhibitoryeffect on NO production, inhibitory effect on cytokine production,inhibitory effect on the increase of nitric oxide concentration in bloodand inhibitory effect on the increase of cytokine concentration.

The composition and the system of the present invention contain ananionic synthetic phospholipid and a naturally-occurring phospholipid inspecific proportions and have a pH adjusted to not more than about 6.Therefore, the inventive Compound, which is a main ingredient, a saltthereof and a prodrug therefor, and the composition and the system ofthe present invention have superior stability, even after sterilizationin an autoclave etc.

Moreover, the composition and the system of the present invention canincrease the concentration of the inventive Compound, a salt thereof anda prodrug therefor, and by controlling the particle size of the dispersephase particles, retentivity in blood, blood vessel permeability andmigration into inflammatory sites can be enhanced. As a result,pharmacokinetics and biodistribution of the inventive Compound, a saltthereof and a prodrug therefor can be improved and targeting becomespossible, which in turn makes effective administration of the drug withsuppressed side effect attainable. Therefore, the composition and thesystem of the present invention are useful for the treatment of thetarget disease particularly by intravenous administration.

1. An emulsion composition comprising (1) a compound of the formula:

wherein R represents an optionally substituted aliphatic hydrocarbongroup, an optionally substituted aromatic hydrocarbon group, anoptionally substituted heterocyclic group, a group represented by theformula: OR¹ wherein R¹ represents a hydrogen atom or an optionallysubstituted aliphatic hydrocarbon group, or a group represented by theformula:

wherein R^(1b) and R^(1c) are each independently a hydrogen atom or anoptionally substituted aliphatic hydrocarbon group, R⁰ represents ahydrogen atom or an optionally substituted aliphatic hydrocarbon group,or taken together, R and R⁰ represent a bond,

wherein n is an integer of 1 to 4, ring A¹ is a cycloalkene optionallysubstituted by 1 to 4 substituents selected from the group consisting of(i) an aliphatic hydrocarbon group optionally having substituents, (ii)an aromatic hydrocarbon group optionally having substituents, (iii) agroup represented by the formula: OR¹ wherein R¹ represents a hydrogenatom or an aliphatic hydrocarbon group optionally having substituents,and (iv) a halogen atom, Ar represents an optionally substitutedaromatic hydrocarbon group, a salt thereof or a prodrug therefor, (2) ananionic synthetic phospholipid in a proportion of about 0.1 to about0.2% weight per total volume relative to the composition in total, and(3) a naturally-occurring phospholipid in a proportion of about 0.1 toabout 10% weight per total volume relative to the composition in total,wherein the emulsion has a pH of not more than about
 6. 2. Thecomposition of claim 1 wherein R, R¹, R^(1b), R^(1c), R⁰, A¹ and Ar maybe substituted with one to four substituents, each substituentindependently selected from the group Q consisting of (i) a 5- to8-membered ring or condensed ring substituent group containing 1 to 4hetero atoms selected from the group consisting of nitrogen atom whichis optionally oxidized, oxygen atom and sulfur atom, wherein said ringis optionally substituted by 1 to 3 substituents selected from the groupconsisting of C₁₋₄ alkyl, hydroxy, oxo and C₁₋₄ alkoxy, (ii) oxosubstituent group, (iii) hydroxyl substituent group, (iv) C₁₋₆ alkoxysubstituent group, (v) C₃₋₁₀ cycloalkyloxy substituent group, (vi) C₆₋₁₀aryloxy substituent group, (vii) C₇₋₁₉ aralkyloxy substituent group,(viii) a 5- to 8-membered ring or condensed ring-oxy substituent groupcontaining 1 to 4 hetero atoms selected from the group consisting ofnitrogen atom which is optionally oxidized, oxygen atom and sulfur atom,wherein said ring-oxy substituent group is optionally substituted by 1to 3 substituents selected from the group consisting of C₁₋₄ alkyl,hydroxy, oxo and C₁₋₄ alkoxy, (ix) C₁₋₆ alkylthio substituent groupwherein the sulfur atom may be optionally oxidized, (x) C₃₋₁₀cycloalkylthio substituent group wherein the sulfur atom may beoptionally oxidized, (xi) C₆₋₁₀ arylthio substituent group wherein thesulfur atom may be optionally oxidized, (xii) C₇₋₁₉ aralkylthiosubstituent group wherein the sulfur atom may be optionally oxidized,(xiii) a 5- to 8-membered ring or condensed ring-thio substituent groupcontaining 1 to 4 hetero atoms selected from the group consisting ofnitrogen atom which is optionally oxidized, oxygen atom and sulfur atom,wherein said ring-thio substituent group is optionally substituted by 1to 3 substituents selected from the group consisting of C₁₋₄ alkyl,hydroxy, oxo and C₁₋₄ alkoxy, (xiv) a 5- to 8-membered ring or condensedring-sulfinyl substituent group containing 1 to 4 hetero atoms selectedfrom the group consisting of nitrogen atom which is optionally oxidized,oxygen atom and sulfur atom, wherein said ring-sulfinyl substituentgroup is optionally substituted by 1 to 3 substituents selected from thegroup consisting of C₁₋₄ alkyl, hydroxy, oxo and C₁₋₄ alkoxy, (xv) a 5-to 8-membered ring group or a condensed ring-sulfonyl group containing 1to 4 hetero atoms selected from the group consisting of nitrogen atomwhich is optionally oxidized, oxygen atom and sulfur atom, wherein saidring-sulfonyl substituent group is optionally substituted by 1 to 3substituents selected from the group consisting of C₁₋₄ alkyl, hydroxy,oxo and C₁₋₄ alkoxy, (xvi) nitro substituent group, (xvii) halogen atom,(xviii) cyano substituent group, (xix) carboxyl substituent group, (xx)C₁₋₁₀ alkoxy-carbonyl substituent group, (xxi) C₃₋₆cycloalkyloxy-carbonyl substituent group, (xxii) C₆₋₁₀ aryloxy-carbonylsubstituent group, (xxiii) C₇₋₁₉ aralkyloxy-carbonyl substituent group,(xxiv) a 5- to 8-membered ring or condensed ring-oxycarbonyl substituentgroup containing 1 to 4 hetero atoms selected from the group consistingof nitrogen atom which is optionally oxidized, oxygen atom and sulfuratom, wherein said ring-oxycarbonyl substituent group is optionallysubstituted by 1 to 3 substituents selected from the group consisting ofC₁₋₄ alkyl, hydroxy, oxo and C₁₋₄ alkoxy, (xxv) C₆₋₁₀ arylcarbonylsubstituent group, (xxvi) C₁₋₆ alkanoyl substituent group, (xxvii) C₃₋₅alkenoyl substituent group, (xxviii) C₆₋₁₀ aryl-carbonyloxy substituentgroup, (xxix) C₂₋₆ alkanoyloxy substituent group, (xxx) C₃₋₅ alkenoyloxysubstituent group, (xxxi) carbamoyl substituent group or cyclicaminocarbonyl substituent group optionally substituted by 1 or 2substituents selected from the group consisting of C₁₋₄ alkyl, phenyl,C₁₋₇ acyl and C₁₋₄ alkoxy-phenyl, (xxxii) thiocarbamoyl substituentgroup optionally substituted by 1 or 2 substituents selected from thegroup consisting of C₁₋₄ alkyl and phenyl, (xxxiii) carbamoyloxysubstituent group optionally substituted by 1 or 2 substituents selectedfrom the group consisting of C₁₋₄ alkyl and phenyl, (xxxiv) C₁₋₆alkanoylamino substituent group, (xxxv) C₆₋₁₀ aryl-carbonylaminosubstituent group, (xxxvi) C₁₋₁₀ alkoxy-carboxamide substituent group,(xxxvii) C₆₋₁₀ aryloxy-carboxamide substituent group, (xxxviii) C₇₋₁₉aralkyloxy-carboxamide substituent group, (xxxix) C₁₋₁₀alkoxy-carbonyloxy substituent group, (xl) C₆₋₁₀ aryloxy-carbonyloxysubstituent group, (xli) C₇₋₁₉ aralkyloxy-carbonyloxy substituent group,(xlii) C₃₋₁₀ cycloalkyloxy-carbonyloxy substituent group, (xliii) ureidosubstituent group optionally substituted by 1 to 3 substituents selectedfrom the group consisting of C₁₋₄ alkyl and phenyl, and (xliv) C₆₋₁₀aryl substituent group optionally having 1 to 4 substituents selectedfrom the group consisting of C₁₋₄ alkyl and phenyl.
 3. The compositionof claim 1, wherein R is (1) {circle around (1)} linear or branchedC₁₋₂₀ alkyl, {circle around (2)} C₃₋₁₀ cycloalkyl, {circle around (3)}C₄₋₁₂ cycloalkylalkyl, {circle around (4)} lower (C₃₋₆) alkenyl group or{circle around (5)} lower (C₃₋₆) alkynyl group optionally having 1 to 4substituents each independently selected from the group Q; wherein whentwo substituents from group Q substitute said linear or branched C₁₋₂₀alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, C₃₋₆ alkenyl or C₃₋₆alkynyl, said substituents may be linked to form a ring; (2) C₆₋₁₄aromatic hydrocarbon group optionally having 1 to 5 substituentsselected from the group consisting of halogen atom, C₁₋₄ alkyl group,C₁₋₄ alkoxy group, C₁₋₄ alkoxy-carbonyl group, carboxyl group, nitrogroup, cyano group, hydroxyl group, C₁₋₄ alkanoylamino group, C₃₋₁₆cycloalkyl group, C₆₋₁₀ aryl group, halogeno C₁₋₄ alkyl group, halogenoC₁₋₄ alkoxy group, C₁₋₄ alkylthio group, C₁₋₄ alkylsulfonyl group, C₁₋₄alkanoyl group, 5-membered aromatic heterocyclic group, carbamoyl group,C₁₋₄ alkyl-carbamoyl group, C₁₋₄ alkoxy-carbonyl-C₁₋₄ alkyl-carbamoylgroup and 1,3-diacylguanidino-C₁₋₄ alkyl group, (3) a 5- to 8-memberedring or a condensed ring group containing 1 to 4 hetero atoms selectedfrom the group consisting of nitrogen atom which is optionally oxidized,oxygen atom and sulfur atom, wherein said ring group optionally has 1 to3 substituents selected from the group consisting of C₁₋₄ alkyl,hydroxy, oxo and C₁₋₄ alkoxy, (4) a group of the formula —OR¹ wherein R¹is (i) hydrogen atom or (ii) {circle around (1)} linear or branchedC₁₋₂₀ alkyl, {circle around (2)} C₃₋₁₀ cycloalkyl, {circle around (3)}C₄₋₁₂ cycloalkylalkyl, {circle around (4)} lower C₃₋₆ alkenyl group or{circle around (5)} lower C₃₋₆ alkynyl group optionally having 1 to 4substituents, each independently selected from the group Q; wherein whentwo substituents from group Q substitute said linear or branched C₁₋₂₀alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, C₃₋₆ alkenyl or C₃₋₆alkynyl, said substituents may be linked to form a ring; or (5) a groupof the formula

wherein R^(1b) and R^(1c) are each independently a (i) hydrogen atom or(ii) {circle around (1)} linear or branched C₁₋₂₀ alkyl, {circle around(2)} C₃₋₁₀ cycloalkyl, {circle around (3)} C₄₋₁₂ cycloalkylalkyl,{circle around (4)} lower C₃₋₆ alkenyl group or {circle around (5)}lower C₃₋₆ alkynyl group optionally substituted with 1 to 4 substituentseach independently selected from the group Q; wherein when twosubstituents from group Q substitute said linear or branched C₁₋₂₀alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, C₃₋₆ alkenyl or C₃₋₆alkynyl, said substituents may be linked to form a ring; R⁰ represents ahydrogen atom, a linear or branched C₁₋₂₀ alkyl, a C₃₋₁₀ cycloalkyl, aC₄₋₁₂ cycloalkylalkyl, a lower (C₃₋₆) alkenyl group or a lower (C₃₋₆)alkynyl group, or R and R⁰ represent a bond with each other, ring A¹represents cycloalkene optionally substituted by 1 to 4 substituents,each independently selected from the group consisting of (1) linear orbranched C₁₋₂₀ alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₂ cycloalkylalkyl, C₃₋₆alkenyl or C₃₋₆ alkynyl; optionally substituted with 1 to 4substituents, each of said substituents independently selected fromsubstituent group Q; wherein when two substituents from group Qsubstitute said linear or branched C₁₋₂₀ alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₂cycloalkylalkyl, C₃₋₆ alkenyl or C₃₋₆ alkynyl, said substituents may belinked to form a ring; (2) a C₆₋₁₄ aromatic hydrocarbon group optionallyhaving 1 to 5 substituents selected from the group consisting of halogenatom, C₁₋₄ alkyl group, C₁₋₄ alkoxy group, C₁₋₄ alkoxy-carbonyl group,carboxyl group, nitro group, cyano group, hydroxyl group, C₁₋₄alkanoylamino group, C₃₋₆ cycloalkyl group, C₆₋₁₀ aryl group, halogenoC₁₋₄ alkyl group, halogeno C₁₋₄ alkoxy group, C₁₋₄ alkylthio group, C₁₋₄alkylsulfonyl group, C₁₋₄ alkanoyl group, 5-membered aromaticheterocyclic group, carbamoyl group, C₁₋₄ alkyl-carbamoyl group, C₁₋₄alkoxy-carbonyl-C₁₋₄ alkyl-carbamoyl group and 1,3-diacylguanidino-C₁₋₄alkyl group; (3) —OR¹ wherein R¹ is (i) hydrogen atom or (ii) {circlearound (1)} linear or branched C₁₋₂₀ alkyl, {circle around (2)} C₃₋₁₀cycloalkyl, {circle around (3)} C₄₋₁₂ cycloalkylalkyl, {circle around(4)} lower C₃₋₆ alkenyl group or {circle around (5)} lower C₃₋₆ alkynylgroup optionally having 1 to 4 substituents, each independently selectedfrom the group Q; wherein when two substituents from group Q substitutesaid linear or branched C₁₋₂₀ alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₂cycloalkylalkyl, C₃₋₆ alkenyl or C₃₋₆ alkynyl, said substituents may belinked to form a ring; (4) halogen atoms and, Ar represents a C₆₋₁₄aromatic hydrocarbon group optionally having 1 to 5 substituentsselected from the group consisting of halogen atom, C₁₋₄ alkyl group,C₁₋₄ alkoxy group, C₁₋₄ alkoxycarbonyl group, carboxyl group, nitrogroup, cyano group, hydroxyl group, C₁₋₄ alkanoylamino group, C₃₋₆cycloalkyl group, C₆₋₁₀ aryl group, halogeno C₁₋₄ alkyl group, halogenoC₁₋₄ alkoxy group, C₁₋₄ alkylthio group, C₁₋₄ alkylsulfonyl group, C₁₋₄alkanoyl group, 5-membered aromatic heterocyclic group, carbamoyl group,C₁₋₄ alkyl-carbamoyl group, C₁₋₄ alkoxycarbonyl-C₁₋₄ alkyl-carbamoylgroup and 1,3-diacylguanidino-C₁₋₄ alkyl group.
 4. The composition ofclaim 1, wherein when two substituents from group Q substitute saidlinear or branched C₁₋₂₀ alkyl, C₃₋₁₀ cycloalkyl, C₄₋₁₂ cycloalkylalkyl,C₃₋₆ alkenyl or C₃₋₆ alkynyl, said substituents may be linked to form aring; wherein said ring is an indanyl group or a1,2,3,4-tetrahydronaphthyl group; and wherein said ring may be furthersubstituted by 1 to 4 substituents each independently selected fromgroup Q.
 5. The composition of claim 1, wherein the compound is selectedfrom the group consisting of d-ethyl6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate,d-ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate,ethyl 6-[N-(2-chlorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate andethyl6-[N-(2-chloro-4-methylphenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, ora salt thereof.
 6. The composition of claim 1, wherein said anionicsynthetic phospholipid is a compound of the formula

wherein R⁶ and R⁷ are the same or different and each is a C₇₋₂₀ chainhydrocarbon group, and R⁸ is

or a salt thereof.
 7. The composition of claim 1, wherein said anionicsynthetic phospholipid is a compound of the formula

wherein m is an integer of 7-20, and R⁸ is

or a salt thereof.
 8. The composition of claim 1, wherein said anionicsynthetic phospholipid is selected from the group consisting ofdimyristoylphosphatidylglycerol, dipalmitoylphosphatidylglycerol,distearoylphosphatidylglycerol, dioleoylphosphatidylglycerol,oleoylpalmitoylphosphatidylglycerol, dioctanoylphosphatidic acid,didecanoylphosphatidic acid, dilauroylphosphatidic acid,dimyristoylphosphatidic acid, dipalmitoylphosphatidic acid,diheptadecanoylphosphatidic acid, distearoylphosphatidic acid,dioleoylphosphatidic acid, arachidonylstearoylphosphatidic acid,dipalmitoylphosphatidylserine, dioleoylphosphatidylserine,dimyristoylphosphatidylinositol, dipalmitoylphosphatidylinositol,distearoylphosphatidylinositol, dioleoylphosphatidylinositol,dimyristoylphosphatidylserine and distearoylphosphatidylserine.
 9. Thecomposition of claim 1, wherein said anionic synthetic phospholipid isdimyristoylphosphatidylglycerol.
 10. The composition of claim 1, whereinsaid naturally-occurring phospholipid is egg yolk lecithin or soybeanlecithin.
 11. The composition of claim 1, wherein saidnaturally-occurring phospholipid is egg yolk lecithin.
 12. Thecomposition of claim 1, wherein said anionic synthetic phospholipid iscontained in a proportion of about 0.2% weight per total volume of thecomposition in total.
 13. The composition of claim 1, wherein compound(I), a salt thereof or a prodrug therefor is in a proportion of about0.001 to about 95 weight percent of the composition in total.
 14. Thecomposition of claim 1, wherein compound (I), a salt thereof or aprodrug therefor is in a proportion of about 0.01 to about 30 weightpercent of the composition in total.
 15. The composition of claim 1,which further comprises a component selected from the group consistingof oil, water and a combination thereof.
 16. The composition of claim15, wherein said oil is selected from the group consisting of vegetableoil, a partially hydrogenated vegetable oil, mono-acid glyceride, mixedacid glyceride and medium-size chain fatty acid glycerine ester.
 17. Thecomposition of claim 15, wherein said oil is a vegetable oil.
 18. Thecomposition of claim 17, wherein said vegetable oil is selected from thegroup consisting of soybean oil, cottonseed oil, rapeseed oil, peanutoil, safflower oil, sesame oil, rice bran oil, corn germ oil, sunfloweroil, poppy oil and olive oil.
 19. The composition of claim 17, whereinsaid vegetable oil is a soybean oil.
 20. The composition of claim 15,wherein said oil is in a proportion of about 1 to about 30 weightpercent of the composition in total.
 21. The composition of claim 1,which further comprises glycerine.
 22. The composition of claim 1, whichis an oil-in-water composition.
 23. The composition of claim 1, whichhas a pH from about 3 to about
 6. 24. The composition of claim 1, whichis for an injection.
 25. A composition comprising: 0.1 to 3% weight pertotal volume of d-ethyl6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, 5to 25% weight per total volume of soybean oil, 1 to 3% weight per totalvolume of egg yolk lecithin, 0.1 to 0.2% weight per total volumedimyristoyl phosphatidylglycerol and water, wherein the composition hasa pH of not more than about
 6. 26. A composition comprising: 0.1 to 3%weight per total volume of d-ethyl6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate, 5to 25% weight per total volume of soybean oil, 1 to 3% weight per totalvolume of egg yolk lecithin, 0.1 to 0.2% weight per total volumedistearoyl phosphatidylglycerol and water, wherein the composition has apH of not more than about
 6. 27. A composition comprising: 1% weight pertotal volume of d-ethyl6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate,20% weight per total volume of soybean oil, 1.2% weight per total volumeof egg yolk lecithin, 0.2% weight per total volume dimyristoylphosphatidylglycerol and water, wherein the composition has a pH of notmore than about
 6. 28. A composition comprising: 1% weight per totalvolume of d-ethyl6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate,20% weight per total volume of soybean oil, 1.2% weight per total volumeof egg yolk lecithin, 0.2% weight per total volume distearoylphosphatidylglycerol and water, wherein the composition has a pH of notmore than about
 6. 29. The composition of claim 1, which comprises adisperse phase particle comprising anionic synthetic phospholipid,naturally-occurring phospholipid, an oil component and compound (I), asalt thereof or a prodrug therefor, and water wherein the disperse phaseparticle is dispersed.
 30. The composition of claim 29, wherein thedisperse phase has an average particle size of about 25 to about 500 nm.31. The composition of claim 1, which is a nitric oxide or cytokineproduction inhibitor, or a nitric oxide inhibitor and a cytokineproduction inhibitor.
 32. The composition of claim 1, which is an agentfor treating cardiac disease, autoimmune disease, sepsis or septicshock.
 33. A method for making an emulsion comprising the steps of: (a)adding an anionic synthetic phospholipid in a proportion of about 0.1 toabout 0.2% weight per total volume relative to the composition in total,and a naturally-occurring phospholipid to a compound represented by theformula:

wherein R represents an optionally substituted aliphatic hydrocarbongroup, an optionally substituted, aromatic hydrocarbon group, anoptionally substituted heterocyclic group, a group represented by theformula: OR¹ wherein R¹ represents a hydrogen atom or an optionallysubstituted aliphatic hydrocarbon group, or a group represented by theformula:

wherein R^(1b) and R^(1c) are each independently a hydrogen atom or anoptionally substituted aliphatic hydrocarbon group, R⁰ represents ahydrogen atom or an optionally substituted aliphatic hydrocarbon group,or taken together, R and R⁰ represent a bond,

wherein n is an integer of 1 to 4, ring A¹ is a cycloalkene optionallysubstituted by 1 to 4 substituents selected from the group consisting of(i) an aliphatic hydrocarbon group optionally having substituents, (ii)an aromatic hydrocarbon group optionally having substituents, (iii) agroup represented by the formula: OR¹ where R¹ represents a hydrogenatom or an aliphatic hydrocarbon group optionally having substituents,and (iv) a halogen atom, Ar represents an optionally substitutedaromatic hydrocarbon group, a salt thereof or a prodrug therefor, in oiland water to form an emulsion; and then, (b) adjusting said emulsion toa pH of not more than 6 to form a stable emulsion.
 34. The method ofclaim 33, whereby stability of said stable emulsion during autoclavesterilization is improved.
 35. A method for treating cardiac disease,autoimmune disease, sepsis or septic shock, comprising administrating toa mammal in need thereof a pharmaceutically effective amount of thecomposition of claim
 1. 36. A method of making a composition of claim 1for manufacturing an agent for preventing or treating cardiac disease,autoimmune disease, sepsis or septic shock comprising introducing saidcompound of formula (I), said anionic synthetic phospholipid, and saidnaturally-occurring phospholipid under conditions sufficient to make anemulsion composition of claim 1.